KR20070024612A - Substituted tetrahydro-2h-isoquinolin-1-one derivatives, method for the production thereof, and use of the same as medicaments - Google Patents

Abstract

The invention relates to compounds of general formula (I), the designations of the substituents R1, R2, Ar and X being cited in the description, and to the physiologically compatible salts thereof. The invention also relates to a method for producing said compounds, and to the use thereof as medicaments. The inventive compounds are poly(ADP-ribose)polymerase (PARP) inhibitors. ® KIPO & WIPO 2007

Description

Substituted tetrahydro-2H-isoquinolin-1-one derivatives, method for the production approximately, and use of the same as medicaments}

The present invention relates to compounds of formula (I, wherein the definitions of substituents R1, R2, Ar and X are specified below), physiologically acceptable salts thereof, methods of preparing these compounds and their pharmaceutical uses .

The compounds are inhibitors of poly (ADP-ribose) polymerase (PARP).

PARP Inhibitory effect on

Poly (adenosine 5'-diphosphate-ribose) polymerase, also known as poly (ADP-ribose) synthase [poly (ADP-ribose) polymerase, PARP] has about 2 x 10 ⁵ molecules per nucleus. , Eukaryotic chromatin-binding nuclear enzyme. Recent studies have shown that PARP is associated with the development of a variety of diseases, so inhibition of PARP enzyme activity may have a beneficial effect on disease progression in clinical animal specimens. Cristina Cosi, Expert Opin. Ther. Patents, 2002, 12, 1047-1071 and L. Virag and C. Szabo, Pharmacol. Rev., 2002, 54, 1-54]. Poly (ADP-ribose) polymerase occurs in all eukaryotic tissues except yeast and is part of a genomic surveillance network that protects genetic information from genotoxic effects. DNA damage causes the enzymatic activity of poly (ADP-ribose) polymerase and allows to correct errors recognized by enzymes in DNA under physiological conditions. However, in pathological conditions, poly (ADP-ribose) polymerase can be extremely activated by free-radical oxygen species-in case of ischemia, hypoxia, reperfusion or inflammatory progression-consumed by a large amount of the enzyme of the substrate NAD do. This depletion of NAD is one of the causes of cell death observed in target tissues (so-called energy crisis theory). The therapeutic use of PARP inhibitors lies in the inhibition or reduction of such NAD depletion in tissues. In addition to the roles as described herein, in the transmission of signals from oxidative stress in cells to NAD depletion, additional cellular actions of APRP have recently been proposed in the literature, and they also likewise demonstrate the role of PARP inhibitory action in pathological conditions. Plays a role in molecular mechanisms. A. Chiarugi, Trends Pharmacol. Sci., 2002, 23, 122-129]. Irrespective of this unresolved discussion of the molecular mechanism of action, the therapeutic efficacy of various PARP inhibitors can be, for example, acute myocardial infarction, acute renal failure, cerebral ischemia (stroke), neurodegenerative diseases (eg, Parkinson's disease), It has been shown in several clinical animal samples for sensitization in diabetes, bioforeign-induced hepatotoxicity, arthritis, pulmonary shock, pulmonary shock and chemotherapy of neoplastic disorders [summarized in L. Virag and C. Szabo, Pharmacol. Rev., 2002, 54, 1-54).

In particular, PARP inhibitors not only cause histological and donor improvements in acute myocardial infarction [J. Bowes et al., Eur. J. Pharmacol., 1998, 359, 143-150; L. Liaudet et al., Br. J. Pharmacol., 2001, 133, 1424-1430; N. Wayman et al., Eur. J. Pharmacol., 2001, 430, 93-100], it is possible to indicate that significantly superior cardiac function is measured in chronic heart disease during PARP inhibitor treatment [P. Pacher, J. Am. Coll. Cardiol., 2002, 40, 1006-1016. This perfusion failure, which impairs the work of tissues through cell death in the infarcted heart, occurs in stroke at the beginning of a chain reaction that causes impairment or complete loss of each area and function of tissues. Thus, genetic elimination of the APRP-1 gene [M.J.L. Eliasson et al., Nat. Med., 1997, 10, 1089-1095] the efficacy of APRP inhibitors other than cerebral ischemia (K. Takahashi et al., L. Cereb. Blood Flow Metab., 1997, 11, 1137-1142], MPTP-induced neurotoxin [C. Cosi et al., Brain Res., 1996, 729, 264-269] and excitatory toxicity of neurons [A.S. Mandir et al., J. Neurosci., 2000, 21, 8005-8011]. A further important finding in connection with cardiovascular disease is the efficacy of PARP inhibition in the ischemia-damaged kidneys, where improvements in tissue filtration are likewise treated with PARP inhibitors compared to subjects treated with placebo. Found in animals [DR: Martin et al., Am. J. Physiol. Regulatory Integrative Comp. Physiol., 2000, 279, R1834-R1840]. In contrast to acute ischemic blockade of the above mentioned diseases, chronic PARP activation occurs in various conditions, such as, for example, diabetes. The efficacy of PARP inhibitors has been described in clinical specimens of type I diabetes [W.L. Suarez-Pinzon et al., Diabetes, 2003, 52, 1683-1688] and clinical specimens of type II diabetes [F.G. Soriano et al., Nat. Med., 2001, 7, 108-113; F.G. Soriano et al., Circulation, 2001, 89, 684-691. The beneficial efficacy of PARP inhibitors in type I diabetes can contribute to their anti-inflammatory properties, which are also referred to as chronic colitis [H.B. Jijon et al., Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 279, G641-G651], collagen-induced arthritis (H. Kroger et al., Inflammation, 1996, 20, 203-215) and pulmonary shock (B. Zingarelli et al. , Shock, 1996, 5, 258-264]. PARP inhibitors also have a sensitizing effect on tumors in chemotherapy in mice (L. Tentori et al., Blood, 2002, 99, 2241-2244).

Prior art

For example, many different classes of compounds, such as indole, benzimidazole, isoquinolinol or derivatives of quinazolinone, can be used as PARP inhibitors. See, eg, C. Cosi, Expert Opin. Ther. patents, 2002, 12, 1047-1071; Southan et al., Current Medicinal Chemistry, 2003, 10, 321-340. Many of the PARP inhibitors already disclosed are derivatives of non- or polycyclic basic structures.

The use of isoquinolinone derivatives as PARP inhibitors is described, for example, in WO 02/090334. The isoquinolinone derivatives described herein are, without exception, the second ring of the bicycle (with 5, 6, 7 and 8 carbon atoms) in aromatic form, and rings with bicyclic amide groups may be optionally hydrogenated at positions 3 and 4 Based on the underlying structure. The isoquinolinone derivatives disclosed in EP 0 355 750, which can likewise be used as PARP inhibitors, are based on the same aromatic base structure.

Many PARP inhibitors can be inferred from Formula I as disclosed in WO 99/11642. In particular, tetrahydro-2H-isoquinolin-1-one derivatives having an aminoethyl substituent at the 4-position are disclosed. Further possibilities for the radical R ⁶ in formula I may be aryl, but it is not mentioned that the aryl radical optionally has further substituents. Aryl radicals for R ⁶ are described in particular only in WO 99/11624, where, for example, the ring defined by Y in the basic structure is unsaturated and has heteroatoms. However, certain combinations of 5,6,7,8-tetrahydro-2H-isoquinolin-1-one derivatives substituted by aryl or heteroaryl radicals either directly or via linkage groups at position 4 are disclosed in WO 99 /. It is neither disclosed nor apparent in 11624. Therefore, the compounds of the present invention are not disclosed in WO 99/11624. The present invention is not directed to compounds which are expressly disclosed in WO 99/11624.

See J. Rigby et al., J. Org. Chem. 1984, 4569-4571, discloses 4-phenyl-5,6,7,8-tetrahydro-2H-iso by the condensation of enamine and vinyl isocyanate within the framework of a general synthesis for the cycling of vinyl isocyanates. The preparation of quinolin-1-ones is described. J. There is no association between the compounds described in Rigby et al. And any use as a medicament. The present invention is described in J. Rigby et al., Et al.

Because diseases such as myocardial infarction that can be treated by the inhibition of PARP represent a serious risk to the health of humans and other mammals, new drugs with favorable therapeutic profiles for the treatment of such diseases are very necessary. Therefore, the present invention is based on the object of providing a novel compound having an inhibitory effect on APRP.

This object is achieved by the tetrahydro-2H-isoquinolin-1-one derivative of formula (I) or a pharmaceutically acceptable salt.

Formula I

In Formula I above,

X is a single bond, O, S, NH or N (C ₁ -C ₃ -alkyl),

R 1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF ₃ , or C ₁ -C ₃ -alkyl optionally substituted by hydroxy, chlorine, methoxy or 1, 2 or 3 fluorine atoms,

R2 is hydrogen, fluorine, -CN, hydroxy, methoxy, -OCF ₃ , -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , or hydroxy Oxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms,

R3 is-(C ₁ -C ₃ -alkyl) -NR4R5, -SO ₂ NR4R5, -C (O) NR4R5, -C (H) = N-OR9, -C (O) R6, -NHC (O) R6 ,-(C ₁ -C ₃ -alkyl) -NHC (O) R 6, -NHSO ₂ R 6,-(C ₁ -C ₃ -alkyl) -NHSO ₂ R 6 or -CH (OH) R 7,

R4 and R5 are independently of each other hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, heteroaryl and heterocyclyl Selected from the group consisting of aryl, heteroaryl, heterocyclyl, -O-aryl, fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NHC (O) (C ₁ -C ₃ -alkyl), -NH ₂ , hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl ), -N (C ₁ -C ₃ -alkyl) ₂ , -NH-aryl, -NH-heteroaryl, -NH-C (O) -heteroaryl, -SO ₂ NH ₂ , -SO ₂ (C _1- C ₃ -alkyl) and -NH-SO ₂ (C ₁ -C ₃ -alkyl), wherein the aryl, heteroaryl and heterocyclyl moieties of these substituents are again fluorine, chlorine, bromine, oxo,- _{CF 3, -OCF 3, -NO 2} , -CN, aryl, _{heteroaryl, -NHC (O) (C 1} -C 3 - alkyl), -COOH, hydroxy, C ₁ -C ₃ - Al Kiel, C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C At least monosubstituted by _1- C ₃ -alkyl) ₂ , or

R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted heterocyclyl, wherein the substituents are aryl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, bromine,- _{CF 3, -OCF 3, -NO 2} , -CN, -C (O) R8, -NHC (O) (C 1 -C 3 - alkyl), -NH _2, hydroxy, C ₁ -C ₃ - alkyl , C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C _3- Alkyl) and -NH-SO ₂ (C ₁ -C ₃ -alkyl), aryl, heterocyclyl and heteroaryl of these substituents are again fluorine, chlorine, bromine, hydroxy, C ₁ -C ₃ - it may be at least monosubstituted with an alkoxy, -alkyl or C ₁ -C ₃

R 6 is unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl, heteroaryl or heterocyclyl, wherein the substituents are fluorine, chlorine, bromine, aryl, heterocyclyl, heteroaryl, —CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NHC (O) (C ₁ -C ₃ -alkyl), -NH ₂ , hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -O-heteroaryl, -O-aryl, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and -NH-SO ₂ (C ₁ -C ₃ -alkyl) and the aryl, heterocyclyl and heteroaryl moieties of these substituents are again fluorine, chlorine At least monosubstituted by, bromine, hydroxy, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy,

R 7 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl and heteroaryl, wherein the substituents are fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R8, -NHC (O) (C ₁ -C ₃ -alkyl), -NH ₂ , hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and -NH-SO ₂ ( C ₁ -C ₃ -alkyl),

R8 is C ₁ -C ₃ -alkoxy, -O-phenyl, C ₁ -C ₃ -alkyl, -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ or phenyl, wherein the phenyl moiety is again fluorine, chlorine, bromine, oxo, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, aryl, heteroaryl, -NHC (O) (C ₁ -C ₃ -Alkyl), -COOH, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) At least monosubstituted by ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C ₁ -C ₃ -alkyl) ₂ There is,

R 9 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl and phenyl, wherein the substituents are fluorine, chlorine, bromine, aryl, heterocyclyl, heteroaryl, —CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NHC (O) (C ₁ -C ₃ -alkyl), C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and -NH-SO ₂ ( C ₁ -C ₃ -alkyl), and the aryl, heterocyclyl and heteroaryl of these substituents are again converted into fluorine, chlorine, bromine, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy At least monosubstituted by

Ar is unsubstituted or at least monosubstituted aryl or heteroaryl, wherein the substituents are fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NH ₂ , -NHC (O) (C ₁ -C ₆ -alkyl), hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -CH ₂ -CH ₂ -CH _2- , -CH _2- OC (O)-, -CH ₂ -C (O) -O-, -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH _2- C (O) —NH—, —NH (C ₁ -C ₆ -alkyl), -N (C ₁ -C ₆ -alkyl) ₂ , -SO ₂ (C ₁ -C ₆ -alkyl), heterocyclyl, Heteroaryl, aryl and R 3, and heterocyclyl, aryl and heteroaryl of these substituents are in turn C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, fluorine, chlorine, bromine, trifluor At least monosubstituted by romoxy, trifluoromethoxy or OH,

Heteroaryl is a 5 to 10 membered aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S,

Aryl is a 5-10 membered aromatic monocycle or bicycle,

Heterocyclyl is a 5 to 10 membered non-aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S,

When X is a single bond, Ar is not unsubstituted phenyl.

Tetrahydro-2H-isoquinolin-1-one derivatives of the present invention of formula (I) are, firstly, the second ring of the isoquinolinone base structure is in hydrogenated form, and secondly, the aryl or heteroaryl substituent is directly or linked to Because it is in position 4 on the isoquinolinone base structure, it differs in an advantageous manner from the already known isoquinolin-1-one-based PARP inhibitors. Most of the isoquinolin-1-one-based PARP inhibitors already published have (substantially) planar aromatic base structures. Many of these planar PARP inhibitors may have DNA-binding or DNA-mediated properties that ensure suboptimal stability profiles (Southan et al., Current Medicinal Chemistry 2003, 10, 321-340). The isoquinolinone base structure in the compounds of the present invention is no longer planar at positions 5, 6, 7 and 8 due to its saturation, and these molecules exhibit an advantageous stability profile compared to the planar aromatic base structure. The presence of aryl or heteroaryl substituents at the 4 position of the base structure has a further beneficial effect on the PARP inhibitory effect of the compounds of the invention.

For example, when groups, moieties, radicals or substituents, such as aryl, heteroaryl, alkyl, alkoxy, etc., exist more than once in a compound of formula (I), they all have the meanings mentioned above independently of one another and each (individual ) May have the same or independent meaning. The following applies to aryl and any other radicals not related to its name as (eg) aryl groups, substituents, moieties or radicals. A further example is a -N (C ₁ -C ₃ -alkyl) ₂ group in which two alkyl substituents may be the same or different (eg two ethyl or one propyl and one methyl).

Substituent in the definition of the compounds of formula (I), for example, the aryl is optionally substituted with additional substituents, for example, C ₁ -C ₆ - by a group such as alkoxy, halogen-alkyl, C ₁ -C ₆ If at least monosubstituted, the selection in the case where the aryl is polysubstituted results from a series of further substituents independent of each other. Thus, for example, where aryl is disubstituted, all combinations of additional substituents are included. Thus, when aryl can be disubstituted, for example, with ethyl, aryl can be mono-substituted with methyl and ethoxy in each case, aryl can be mono-substituted with ethyl and fluorine in each case, Aryl can be disubstituted with methoxy and the like.

Alkyl radicals may be linear or branched, bicyclic or cyclic. This also applies when they are part of another group or substituted, for example an alkoxy group (C ₁ -C ₁₀ -alkyl-O—), an alkoxycarbonyl group or an amino group.

Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl. N isomers of these radicals and isopropyl, isobutyl, isopentyl, secondary-butyl, tert-butyl, neopentyl, 3,3-dimethylbutyl and the like are all included here. Unless stated otherwise, alkyl is unsubstituted or optionally substituted by one or more additional radicals, eg, 1, 2, 3 or 4 identical or different radicals, eg, aryl, heteroaryl, alkoxy or halogen Further comprises an alkyl radical. It is also possible for further substituents to occur at any desired position of the alkyl radical. In addition, alkyl includes cycloalkyl and cycloalkylalkyl, wherein alkyl is again substituted by cycloalkyl, and cycloalkyl has three or more carbon atoms. Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. The ring system may also be polycyclic, such as dicalinyl, norbornanyl, bornanyl or adamantanyl, if desired. Cycloalkyl radicals may be unsubstituted or optionally substituted by one or more further radicals, as mentioned above, for example, alkyl radicals.

Examples of alkenyl and alkynyl groups include vinyl, 1-propenyl, 2-propenyl (allyl), 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, ethynyl, 2-propynyl (propargyl), 2-butynyl or 3-butynyl. In addition, alkenyl as shown herein includes cycloalkenyl radicals and cycloalkenylalkyl radicals containing at least three carbon atoms, wherein alkyl is substituted by cycloalkenyl. Examples of cycloalkenyl are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclotenyl.

Alkenyl radicals may have from 1 to 3 paired or unpaired double bonds (ie alky-dienyl and alk-trienyl radicals), preferably one double bond of a linear or branched chain, which Applies to triple bonds to alkynyl radicals. Alkenyl and alkynyl radicals may be unsubstituted or optionally substituted by one or more additional radicals, as mentioned above, for example alkyl radicals.

Unless stated otherwise, the aryl, heteroaryl and heterocyclyl radicals mentioned above may be unsubstituted or may have one or more, for example, one, two, three or four, substituents mentioned above at any position. . For example, substituents on monosubstituted phenyl radicals may be present at positions 2, 3 or 4, and substituents on disubstituted phenyl radicals may be at positions 2, 3, 2,4, 2,5, 2,6 Position, 3,4 position or 3,5 position. Substituents in the trisubstituted phenyl radicals are in 2,3,4 position, 2,3,5 position, 2,3,6 position, 2,4,5 position, 2,4,6 position or 3,4,5 position May exist in Substituents in tetrasubstituted phenyl radicals may be present at the 2,3,4,5 position, the 2,3,4,6 position or the 2,3,5,6 position.

The following definitions for monovalent radical mentioned above apply to divalent radicals such as phenylene, naphthylene or heteroarylene in exactly the same way. Such divalent radicals (parts) may be bonded to adjacent groups for any desired ring carbon atoms. In the case of a phenylene radical, it may be present in the 1,2 position (ortho-phenylene), 1,3 position (meth-phenylene) or 1,4 position (para-phenylene). For example, in a five-membered aromatic system containing heteroatoms such as thiophene or furan, two free bonds may be present at the 2,3, 2,4, 2,5 or 3,4 position. For example, a divalent radical derived from a six-membered aromatic system containing heteroatoms such as pyridine can be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 It may be a pyridinediyl radical. In the case of asymmetric divalent radicals, the invention also includes isomers of all positions. That is, for example, in the case of a 2,3-pyridindiyl radical, one adjacent group is present at position 2 and another adjacent group is included at position 3 as well as one adjacent group is present at position 3 And compounds in which another adjacent group is in the 2 position.

Unless stated otherwise, the rings formed by heteroaryl radicals, heteroarylene radicals, heterocyclyl radicals and heterocyclene radicals and two groups bonded to nitrogen are preferably 1, 2, 3 which may be different or identical Or derived from a fully saturated, partially or wholly unsaturated heterocycle (ie, heterocycloalkane, heterocycloalkene, heteroaromatic) containing four heteroatoms. These are preferably derived from heterocycles comprising 1, 2 or 3, particularly preferably 1 or 2 heteroatoms, which may be the same or different. Unless stated otherwise, heterocycles are mono- or polycyclic, eg, monocyclic, bicyclic or tricyclic. These are preferably monocyclic or acyclic. 5-, 6- or 7-membered rings are preferred, and 5- or 6-membered rings are particularly preferred. In the case of polycyclic heterocycles having two or more heteroatoms, they can all occur in the same ring or can be distributed over multiple rings.

Radicals named heteroaryl in the present invention are derived from monocyclic or bicyclic aromatic heterocycles. Examples of heteroaryl include pyrrolyl, furanyl (= furyl), thiophenyl (= thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1, 3-oxazolyl (= oxazolyl), 1,2-oxazolyl (= isooxazolyl), oxdiazolyl, 1,3-thiazolyl (= thiazolyl), 1,2-thiazolyl (= isothiazolyl ), Tetrazolyl, pyridinyl (= pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl , 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalin Nil, phthalazinyl, thienothiophenyl, 1,8-naphthyridinyl, other naphthyridinyl, putridinyl or thiazolo [3,2-b] [1,2,4] -thiazolyl. When the system is non-monocyclic, saturated forms (perhydro form), partially unsaturated forms (e.g., dihydro form or tetrahydro form), or most unsaturated (nonaromatic) forms, As long as known and stable, they are included for the second ring for each of the aforementioned heteroaryls. Thus, heteroaryl also includes, for example, bicyclic radicals in which two rings are aromatic or bicyclic radicals in which only one ring is aromatic. Examples of such heteroaryls are 3H-indolinyl, 2 (1H) -quinolinonyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxyisoquinolinyl, 1,2-dihydroqui Nolinyl, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, chromonyl, chromamanyl, 1,3-benzodioxolyl, auxin Doryl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6-dihydroquinolinyl, 5,6-dihydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl Or 5,6,7,8-tetrahydroisoquinolyl.

Radicals referred to herein as heterocyclyls are derived from monocyclic or bicyclic nonaromatic heterocycles. As used herein, nonaromatic heterocycle means especially heterocycloalkane (fully saturated heterocycle) and heterocycloalkene (partially unsaturated heterocycle). In the case of heterocycloalkenes, compounds which have two or more double bonds and can also optionally be conjugated together are also included. Examples of heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, isoxazolidinyl, oxazolidinyl, tetrahydrofuranyl, Tetrahydrothiophenyl, 1,3-dioxalanyl, 1,4-dioxyyl, pyranyl, thiopyranyl, tetrahydro-1,2-oxazinyl, tetrahydro-1,3-oxazinyl, mor Polyyl, thiomorpholinyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, azefinyl, 1,2-diazepinyl, 1,3-diazepynyl, 1 , 4-diazepinyl, 1,3-oxazepineyl, 1,3-thiazepinyl, azepanyl, 2-oxoazpanyl, 1,2,3,4-tetrahydropyridinyl, 1,2-di Hydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 4 (3H) -pyrimidonyl, 1,4,5,6-tetrahydropyrimidinyl, 2 -Pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 3,4-dihydro-2H- Ranil, dihydro furanyl, 7-oxa-bicyclo [2.2.1] heptenyl, dihydro-thio phenyl and dihydro-thio pyranyl. The saturation of heterocyclic groups is shown in each definition.

Substituents derived from such heterocycles may be linked via any suitable carbon atom, and further substituents may be included. Radicals derived from nitrogen-containing heterocycles may have a hydrogen atom or another substituent on the corresponding nitrogen atom. Examples include pyrrole, imidazole, pyrrolidine, morpholine, piperazine radicals and the like. Such nitrogen-containing heterocyclic radicals may also be bonded via the nitrogen atom of the ring, especially when the corresponding heterocyclic radical is bonded to a carbon atom. For example, the thienyl radical is in the form of 2-thienyl or 3-thienyl, or in the form of 1-piperidinyl (piperidino), 2-piperidinyl, 3-piperidinyl or 4-piperidinyl It may be a piperidinyl radical of. Suitable nitrogen-containing heterocycles may also be in the form of N-oxides of quaternary salts with counter ions derived from physiologically acceptable acids. For example, pyridinyl radicals may be in the form of pyridine N-oxides. Suitable sulfur-containing heterocycles may also be in the form of S-oxides or S-S-dioxides.

Radicals referred to herein as aryl are derived from monocyclic or bicyclic aromatic systems that do not contain heteroatoms of the ring. If the system is non-monocyclic, the saturated form (perhydro form), partially unsaturated form (eg, dihydro form or tetrahydro form) may also be used as aryl as long as each form is known and stable. Included for two rings. Aryl also includes, for example, a bicyclic radical in which both rings are aromatic, or a bicyclic radical in which only one ring is aromatic. Examples of aryl are phenyl, naphthyl, indanyl, 1,2-dihydronaphthenyl, 1,4-dihydronaphthenyl, indenyl or 1,2,3,4-tetrahydronaphthyl.

Aralkyl (eg aryl- (C ₁ -C ₆ -alkyl)-) means that the alkyl radical (eg C ₁ -C ₆ -alkyl) is again substituted by an aryl radical. Heteroarylalkyl (eg, heteroaryl- (C ₁ -C ₆ -alkyl)-) means that the alkyl radical (eg C ₁ -C ₆ -alkyl) is again substituted by a heteroaryl radical. . See above definitions for the definitions of alkyl, heteroaryl, heterocyclyl and aryl and possible substituents.

In the case of Ar, divalent substituents in which two free valences are not located on the (carbon) atom, such as -Ch ₂ -CH ₂ -CH _2- (propylene) or -CH ₂ -OC (O)-, are defined herein In this case, this means that these divalent substituents, together with the two free valences, are bonded to the same radical (eg Ar), leading to the formation of a (additional) ring. Divalent substituents are usually bonded to different atoms of the same radical, but may optionally be bonded to the same atom of the radical by two free valences, if possible.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or fluorine, particularly preferably fluorine or chlorine.

The present invention includes all stereoisomeric forms of the compounds of formula (I). The asymmetric carbon atoms in the compound of formula (I) may have an S configuration or an R configuration independently of each other. The present invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, eg, mixtures of enantiomers and / or diastereomers in all content and ratios. Thus, the compounds of the present invention present as enantiomers can be in the form of pure enantiomers, racemates and mixtures of two or more enantiomers in all proportions as right and left rotatable enantiomers. In the case of cis / trans isomers, the preparation of the respective stereoisomers is optionally carried out by the use of stereochemically pure starting materials for the synthesis, by separating the mixture by conventional methods, for example by chromatography or crystallization. Through, or by stereoselective synthesis. Separation of mixtures of stereoisomers can be carried out with compounds of formula (I) or with suitable intermediates during synthesis. The present invention further encompasses all tautomeric forms of the compounds of formula (I), in particular keto / enol tautomers. That is, the same compound may be in its keto form, enol form or mixtures thereof in all ratios.

When the compound of formula (I) comprises one or more acid or base groups, the invention also includes correspondingly physiologically or toxicologically acceptable salts.

Physiologically acceptable salts are particularly suitable for medical applications because their solubility in water is greater than that of the starting or basic compounds. Such salts should have a physiologically acceptable anion or cation. Suitable salts of the compounds of the present invention with physiologically acceptable acid additions are inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid and, for example, acetic acid, theophyllic acid, methylenebis-b- Oxynaphthoic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, salicylic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p- Salts of organic acids such as toluenesulfonic acid, tartaric acid and trifluoroacetic acid. Pharmaceutically acceptable suitable basic salts are ammonium salts, alkali metal salts (eg sodium and potassium salts) and alkaline earth metal salts (eg magnesium and calcium salts).

Salts with pharmaceutically unacceptable anions likewise fall within the scope of the invention as intermediates useful for the preparation or purification of pharmaceutically acceptable salts and / or for non-treatments, for example for laboratories.

When the compounds of the formula (I) comprise acidic and basic groups in the same molecule, the invention also encompasses intramolecular salts or betaines (zwitterions) in addition to the salt forms previously specified.

Corresponding salts of compounds of formula (I) can be obtained by conventional methods known to those skilled in the art, for example by reacting organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. have.

The invention further relates to derivatives, including all solvent compounds of formula (I), for example hydrides or alcohol additives, active metabolites of compounds of formula (I), and physiologically acceptable groups that can be removed , Esters or amides.

As used herein, "physiologically functional derivatives" are all physiologically acceptable derivatives of the compounds of the invention of formula (I), eg, compounds of formula (I) or their administration when administered to a mammal (eg, a human) By esters capable of forming active metabolites.

Physiologically functional derivatives also include prodrugs of the compounds of the invention. Such prodrugs can be metabolized into compounds of the present invention in the human body. Such prodrugs may or may not be active on their own, and likewise, the present invention relates to them.

The compounds of the present invention may also exist in various polymorphic forms, for example amorphous and crystalline polymorphs. All polymorphic forms of the compounds of the invention fall within the scope of the invention and are further aspects of the invention.

Preferred are compounds of formula (I) in which one, at least one or all of the above-mentioned R ¹ to R ⁸ , X, Ar, heteroaryl, heterocyclyl and aryl, independently of one another, has the meanings (definitions) described below, The present invention relates to all possible combinations of preferred, more preferred, even more preferred, very more preferred and particularly preferred meanings (definitions) as in the combination with substituents in their basic meaning.

X is preferably a single bond, NH or N (C ₁ -C ₃ -alkyl),

X is particularly preferably a single bond or NH,

R 1 is preferably hydrogen or hydroxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms,

R 2 is preferably hydrogen, fluorine, —OCF ₃ , hydroxy, methoxy, —NH ₂ or C ₁ -C ₃ -alkyl,

R2 is particularly preferably hydrogen,

Ar is preferably unsubstituted or at least monosubstituted phenyl or heteroaryl,

Wherein the substituent is fluorine, chlorine, -CF ₃ , -OCF ₃ , C (O) (C ₁ -C ₃ -alkyl), -NH ₂ , -NHC (O) (C ₁ -C ₃ -alkyl), hydroxy Roxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -CH ₂ -CH ₂ -CH _2- , -CH ₂ -OC (O)-, -CH ₂ -C (O) -O- , -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH ₂ -C (O) -NH-, -NH (C ₁ -C _3- Alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), heterocyclyl, heteroaryl, aryl, and R 3, wherein among these substituents hetero cycle, and heteroaryl is again C ₁ -C ₃ - may be at least monosubstituted with an alkoxy, a fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or OH - alkyl, C ₁ -C _3.

Ar is more preferably unsubstituted or at least monosubstituted phenyl, thienyl, furanyl or pyridinyl,

Wherein the substituent is fluorine, chlorine, -CF ₃ , -OCF ₃ , C (O) (C ₁ -C ₃ -alkyl), -NH ₂ , -NHC (O) (C ₁ -C ₃ -alkyl), hydroxy Roxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -CH ₂ -CH ₂ -CH _2- , -CH ₂ -OC (O)-, -CH ₂ -C (O) -O- , -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH ₂ -C (O) -NH-, -NH (C ₁ -C _3- Alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and R ₃ ,

Ar is more preferably monosubstituted phenyl, thienyl, furanyl or pyridinyl,

Wherein the substituent is fluorine, chlorine, -CF ₃ , -OCF ₃ , C (O) (C ₁ -C ₃ -alkyl), -NH ₂ , -NHC (O) (C ₁ -C ₃ -alkyl), hydroxy Roxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C _1- C ₃ -alkyl) and R ₃ ,

Substituents and X are at meta positions relative to each other, which means that the Ar moiety of the compound of formula (I)-Ar by the above definition-is substituted by one substituent, and Ar is again substituted by X at the meta position for this substituent It can be understood to mean substituted. Meta substitution does not depend on the position of the heteroatom of Ar.

Ar is more preferably monosubstituted phenyl, thienyl, furanyl or pyridinyl,

Where the substituents are fluorine, chlorine, -OCF ₃ , -C (O) CH ₃ , -NHC (O) CH ₃ , hydroxy, -N (CH ₃ ) ₂ , ethoxy, -SO ₂ CH ₃ and R3 And these substituents and X are at meta positions relative to each other.

Ar is particularly preferably furanyl monosubstituted by R 3, and R 3 and X are in a meta position relative to each other.

And R3 is preferably a _{-CH 2 -NR4R5, -SO 2 NR4R5,} -C (O) NR4R5, -CH 2 NHC (O) R6, -CH 2 -NHSO 2 R6 or -CH (OH) R7,

And R3 is more preferably _{-CH 2 -NR4R5, -C (O)} NR4R5, -CH 2 -NHC (O) R6, CH 2 -NHSO 2 R6 or -CH (OH) R7,

R 3 is more preferably -CH ₂ -NR ₄ R ₅ , -C (O) NR 4 R 5 or -CH (OH) R 7,

R 3 is particularly preferably -CH ₂ -NR ₄ R 5,

R 4 and R 5 independently of one another are preferably a group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, indanyl, heterocyclyl and heteroaryl Wherein the substituent is phenyl, heteroaryl, heterocyclyl, -O-phenyl, fluorine, -CN, -C (O) NH ₂ , -C (O) (C ₁ -C ₃ -alkyl), -C (O) -phenyl, -N (C ₁ -C ₃ -alkyl), -C (O) -phenyl, -N (C ₁ -C ₃ -alkyl) ₂ , -NH (C ₁ -C _3- Alkyl), -NH ₂ , -NH-heteroaryl, -NH-C (O) -heteroaryl, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkoxy and hydroxy, and The phenyl, heterocyclyl and heteroaryl moieties in the substituents are again fluorine, chlorine, bromine, oxo, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, phenyl, pyrimidinyl, -NHC (O) (C ₁ -C ₃ -alkyl), -COOH, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl),- SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ - alkyl) or N - it may be substituted with at least one by a (C ₁ -C ₃ alkyl) _2,

R 4 and R 5 together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted heterocyclyl, wherein the substituents are phenyl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, —C (O) ( C ₁ -C ₃ -alkyl), -C (O) -phenyl and hydroxy, of which the phenyl, heterocyclyl and heteroaryl moieties are again converted into fluorine or C ₁ -C ₃ -alkyl At least monosubstituted by

R 4 is more preferably selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, indanyl, heterocyclyl and heteroaryl, Wherein the substituent is phenyl, heteroaryl, heterocyclyl, -O-phenyl, fluorine, -CN, -C (O) NH ₂ , -C (O) (C ₁ -C ₃ -alkyl), -C (O ) -Phenyl, -N (C ₁ -C ₃ -alkyl) ₂ , -NH (C ₁ -C ₃ -alkyl), -NH ₂ , -NH-heteroaryl, -NH-C (O) -heteroaryl, Selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkoxy and hydroxy, of which the phenyl, heterocyclyl and heteroaryl moieties are again fluorine, chlorine, bromine, oxo, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, phenyl, pyrimidinyl, -NHC (O) (C ₁ -C ₃ -alkyl), -COOH, hydroxy, C ₁ -C ₃ -alkyl, C _1- C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , May be substituted by -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C ₁ -C ₃ -alkyl) ₂ , wherein R 5 is Hydrogen,

R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted heterocyclyl, wherein the substituents are phenyl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, -C (O) (C ₁ -C ₃ -alkyl), -C (O) -phenyl and hydroxy, wherein the phenyl, heterocyclyl and heteroaryl moieties of this substituent are again fluorine or C ₁ -C ₃ -alkyl At least monosubstituted by

R 4 is even more preferably hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, cyclohexenyl, indanyl, phenyl, pyrrolidinyl, pyrrolyl, pyrazolyl, furanyl and piperidinyl Selected from the group consisting of fluorine, -CN, -C (O) NH ₂ , -O-phenyl, -C (O) -phenyl, -N (CH ₃ ) ₂ , C ₁ -C _3- Alkyl, C ₁ -C ₃ -alkoxy, hydroxy, unsubstituted or at least monosubstituted phenyl, pyrimidinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl , Morpholinyl, pyrrolidinyl, 1,3-benzodioxolyl, piperidinyl, tetrahydropyranyl, triazolyl, thiazolyl, thiazolidinyl, isoxoxazolyl and dihydroisooxazolyl and, all of which are again a fluorine, chlorine, _{oxo, CF 3, -OCF 3, -NO} 2, phenyl, _{pyrimidinyl, -NHC (O) CH 3,} -COOH, hydroxyl, C ₁ -C ₃ - alkyl, C ₁ -C ₃ -alkoxy, —SO ₂ NH ₂ , —C (O) NH ₂ and —N (CH ₃ ) ₂ , and R 5 is hydrogen,

R4 and R5 together with the nitrogen atom to which they are attached form a radical selected from the group consisting of unsubstituted or at least monosubstituted piperidinyl, pyrrolidinyl, morpholinyl and piperazinyl, wherein the substituents are fluorine,- C (O) (C ₁ -C ₃ -alkyl), oxo, C ₁ -C ₃ -alkyl, hydroxy, unsubstituted or at least monosubstituted phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl And pyrrolidinyl, their substituents are again fluorine or C ₁ -C ₃ -alkyl,

R 4 is particularly preferably unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl wherein the substituents are —N (CH ₃ ) ₂ , hydroxy, unsubstituted or at least monosubstituted phenyl, pyrimidinyl, Imidazolyl, indolyl, benzimidazolyl, pyrazolyl and pyrrolidinyl, and their substituents are again -NHC (O) CH ₃ , C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ and -C (O) NH ₂ , and R 5 is hydrogen, or

R 4 and R 5 together with the nitrogen atom to which they are attached form a radical selected from the group consisting of unsubstituted or at least monosubstituted pyrrolidinyl, piperidinyl and piperazinyl, wherein the substituents are C ₁ -C ₃ -alkyl Is selected from the group consisting of hydroxy and pyrrolidinyl,

R 6 is preferably unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl or heteroaryl, wherein the substituents are fluorine, chlorine, bromine, —CF ₃ , —OCF ₃ , —NHC (O) ( C ₁ -C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -O-heteroaryl, phenyl, -NH ₂ , -NH (C ₁ -C ₃ -alkyl ), -N (C ₁ -C ₃ -alkyl) ₂ and heterocyclyl, of which substituents phenyl, heteroaryl and heterocyclyl are again fluorine, chlorine, bromine, hydroxy, C ₁ -C ₃ - it may be at least monosubstituted with an alkoxy, -alkyl or C ₁ -C ₃

R 6 is more preferably —CF ₃ or unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, pyridinyl, furanyl or phenyl, wherein the substituent is fluorine, —NHC (O) (C ₁ -C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy and -O-pyridinyl,

R 6 is particularly preferably C ₁ -C ₆ -alkyl, pyridinyl, -CF ₃ , furanyl or phenyl, and phenyl is optionally substituted by -NH (O) CH ₃ , -O-pyridinyl or methoxy Can,

R 7 is preferably selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl and pyridinyl, wherein the substituents are fluorine, chlorine, bromine, hydroxy, C ₁ -C ₃ - alkyl and C ₁ -C ₃ - is selected from the group consisting of alkoxy,

R7 is particularly preferably hydrogen,

R9 is preferably hydrogen or pyrrolidinylethyl,

Aryl is preferably phenyl, indanyl or naphthyl,

Aryl is more preferably phenyl or indanyl,

Aryl is particularly preferably phenyl,

Heteroaryl is preferably pyridinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl, 1,3-benzodioxolyl, triazolyl, thiazolyl, isoxa Zolyl, pyrrolyl, pyrazinyl, oxazolyl, pyridazinyl, quinolinyl, isoquinolyl, benzofuranyl, 3-oxo-1,3-dihydroisobenzofuranyl or 4,5,6,7- Tetrahydrobenzothiazolyl,

Heteroaryl is more preferably pyridinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, benzimidazolyl, pyrazolyl, thiazolyl, isoxazolyl, pyrrolyl, pyrazinyl, 3-oxo-1 , 3-dihydroisobenzofuranyl or 4,5,6,7-tetrahydrobenzothiazolyl,

Heteroaryl is particularly preferably pyridinyl, thienyl, pyrazolyl, furanyl or benzimidazolyl,

Heterocyclyl is preferably morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, dihydroisooxazolyl, piperazinyl or tetrahydrofuranyl,

Heterocyclyl is particularly preferably morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl,

Examples of embodiments having preferred compounds of formula (I) with respect to the meanings (definitions) described above are as follows:

i) R1 to R7, X, Ar, heteroaryl and heterocyclyl each have their preferred meanings, or

ii) R 1 has its preferred meaning and all other substituents have their basic meanings, or

iii) R 2 has its preferred meaning and all other substituents have their basic meaning, or

iv) R 3 has its preferred meaning and R 1, R 2, R 4 to R 8, X, Ar, heteroaryl, heterocyclyl and aryl have their basic meanings, or

v) R4 and R5 each have their preferred meanings and all other substituents have their basic meanings, or

vi) R6 has its preferred meaning and all other substituents have their basic meanings, or

vii) R7 has its preferred meaning and all other substituents have their basic meanings, or

viii) R9 has its preferred meaning and all other substituents have their basic meanings, or

ix) X has its preferred meaning, all other substituents have their basic meaning, or

x) Ar has its preferred meaning, all other substituents have their basic meaning, or

xi) aryl has its preferred meaning, all other substituents have their basic meaning, or

xii) heteroaryl has its preferred meaning, all other substituents have their basic meaning, or

xiii) heterocyclyl has its preferred meaning, all other substituents have their basic meaning, or

xiv) aryl, heterocyclyl and heteroaryl each have their preferred meanings and all other substituents have their basic meanings, or

xv) R4 to R7 and R9 have their preferred meanings and all other substituents have their basic meanings, or

xvi) R6 and Ar each have their preferred meanings, and R1-R5, R7, X, heteroaryl and heterocyclyl each have their preferred meanings, or

xvii) R1 and R2 each have their particularly preferred meaning, Ar has their even more preferred meanings, and R3, R4, R6 and heteroaryl each have their more preferred meanings, R7, X and heterocyclyl Each have their preferred meaning, or

xviii) R1, R2, R7 and X each have their particularly preferred meaning and R3, R4 and Ar each have their even more preferred meaning, or

xix) R1 to R4 and X each have their particularly preferred meaning, and Ar has a much more preferred meaning thereof, or

xx) R1 to R4 and X each have their particularly preferred meaning, or

xxi) R1 to R3, X and Ar each have their particularly preferred meaning, and R4 has its much more preferred meaning, or

xxii) R1, R2 and X each have their preferred meanings, R4 has their more preferred meanings, Ar has a much more preferred meaning thereof, and R3, heteroaryl and heterocyclyl each have their particularly preferred meanings , Or

xxiii) R1, R2, X, heteroaryl and heterocyclyl each have their particularly preferred meanings, R4 and Ar each have their more preferred meanings, R3 has their very more preferred meanings and R7 has Have a desirable meaning,

xxiv) R1, R2 and R7 each have their particularly preferred meanings, R3 has their much more preferred meanings, and R4, R6, Ar and heteroaryl each have their more preferred meanings, X and heterocyclyl Has its preferred meaning, or

xxv) R1, R2 and Ar each have their particularly preferred meanings, R3, R7, X and heterocyclyl each have their preferred meanings and R4, R6 and heteroaryl have their more preferred meanings respectively. Or

xxvi) R1, R2, R4, R5, R7, X, heteroaryl and heterocyclyl each have their preferred meanings, Ar has a much more preferred meaning thereof, R6 has its more preferred meanings, R3 and R9 has their basic meaning, or

xxvii) R 1, R 2, X, Ar, heteroaryl and heterocyclyl each have their preferred meanings, R 3, R 4 and R 6 each have their more preferred meanings and R 7 has their particularly preferred meanings, or

xxviii) R1 to R7, X, heteroaryl, heterocyclyl and aryl each have their preferred meanings, and Ar has the basic meaning thereof, or

xxix) R1, R2, X, heteroaryl, heterocyclyl and aryl each have their preferred meanings, R3, R4 and R6 each have their more preferred meanings and R7 has their particularly preferred meanings, Ar Has its basic meaning, or

xxx) R1, R2, R4 to R7, R9, X, heteroaryl and heterocyclyl each have their preferred meanings, Ar has their more preferred meanings, and R3 has its basic meanings, or

xxxi) R1, R2, R9, X, heteroaryl and heterocyclyl each have their preferred meanings, R4, R6 and Ar each have their more preferred meanings, R7 has their particularly preferred meanings, R3 Has its basic meaning, or

xxxii) R3 to R7, Ar, heteroaryl and heterocyclyl each have their preferred meanings, and R1, R2 and X each have their basic meanings, or

xxxiii) Ar has a much more preferred meaning thereof, X, aryl, heteroaryl and heterocyclyl each have their preferred meanings, and all other substituents have their basic meanings, or

xxxiv) X, aryl, heteroaryl and heterocyclyl each have their preferred meanings, R3, R4 and R6 each have their more preferred meanings, R7 has their particularly preferred meanings, and R1, R2 and Ar Each has their basic meaning.

As described above, preferred compounds of formula I are not limited to the examples mentioned above. On the other hand, all combinations of each substituent in the basic sense with other substituents in the preferred, more preferred, more preferred, very more preferred or particularly preferred meanings, or the preferred, more preferred, more preferred of each substituent not described by way of example above All combinations of the more preferred, very more preferred or particularly preferred meanings are also aspects of the invention. This procedure applies only if the definition of each substituent allows the combination.

Most preferred compounds of formula I are 4- (3-methanesulfonylphenylamino) -3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (3-acetylphenyl Amino) -3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (5-butylaminomethylfuran-2-yl) -3-methyl-5,6, 7,8-tetrahydro-2H-isoquinolin-1-one, 3-methyl-4- (5-pyrrolidin-1-ylmethylfuran-2-yl) -5,6,7,8-tetrahydro -2H-isoquinolin-1-one, 4- [5- (3-hydroxypyrrolidin-1-ylmethyl) furan-2-yl] -5,6,7,8-tetrahydro-2H-iso Quinolin-1-one, 4- (5-{[(4-pyrrolidin-1-ylpiperidin-1-ylmethyl) amino] methyl} furan-2-yl) -5,6,7,8- Tetrahydro-2H-isoquinolin-1-one, 4- {5-[(2-dimethylaminoethylamino) methyl] -furan-2-yl) -5,6,7,8-tetrahydro-2H-iso Quinolin-1-one, 4- {5-[(2-hydroxy-2-phenylethylamino) methyl] furan-2-yl} -5,6,7,8-tetrahydro-2H-isoquinoline-1 -One, 4- (5-{[(4-methylpiperazin-1-yl Yl) amino] methyl} furan-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (5-{[(1-methyl-1H-pyrazole- 4-ylmethyl) amino] methyl} furan-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (5-butylaminomethylfuran-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one and 4- (5-hydroxymethylfuran-2-yl) -3-methyl-5,6,7,8-tetrahydro -2H-isoquinolin-1-one.

Compounds of formula (I) can likewise be prepared by various chemical methods belonging to the invention. Some typical methods are outlined in the reaction sequence called Schemes 1 to 3 below. Substituent R is defined herein as described above unless otherwise indicated in each case. Starting compounds and intermediate compounds (intermediates) are either commercially available or can be prepared by methods known to those skilled in the art.

Intermediates of formula II can be obtained by heating phthalic anhydride with amino acid esters. Subsequent treatment of phthalimide of formula (II) with sodium methanolate in methanol under reflux provides an intermediate of formula (III) which is converted to isoquinolinone of formula (IV) after reductive dehydration with red phosphorus in hydroiodic acid do. Partial hydrogenation of these intermediates, some of which are commercially available (eg R 1 = H) or which may be prepared by another method, provides tetrahydroisoquinolinones of formula V. Intermediates of formula VI may be brominated (e.g., with N-bromic acid in methanol or bromine in chloroform as a solvent) and subsequent O-alkylation (e.g., addition of silver carbonate) Together with methyl iodide) in chloroform. Intermediates of formula (VII) are palladium-catalyzed borylation (e.g. palladium dichloride 1,2'-bis (diphenylphosphino) ferrocene as catalyst, triethylamine as base, 1,4-dioxane as 4 By reaction with, 4,5,5-tetramethyl-1,3,2-dioxaborolane). Both intermediates of formula (VI) and (VII) are suitable for further reactions providing compounds of formula (I) (see Schemes 2 and 3). The radical R 2 may optionally be modified during or following any reaction step in Schemes 1 to 3 by means known to those skilled in the art.

Compounds of formula (VIII) wherein X is NH or N (C ₁ -C ₃ -alkyl) are prepared by Hartwig-Buchwald amination with an aromatic amine catalyzed by palladium (E.g., as palladium dibenzylideneacetone using bis (tert-butyl) biphenylphosphine as catalyst in toluene and potassium tert-butanolate as base). Compounds of formula (VIII) wherein X is O and S are copper catalysts (e.g. copper chloride in copper chloride (I), copper oxide (I) or copper powder in high boiling point solvents such as DMF or collidine) It can be prepared by reacting potassium phenolate or sodium or potassium thiophenolate. Removal of the methyl group from the compound of formula VIII (eg by trimethylchlorosilane and potassium iodide in acetonitrile) provides a compound of formula Ia (Scheme 2). In this case, the heteroaryl / aryl moiety (Ar) may be unsubstituted (R ′ = H) or at least monosubstituted, where the substituents are listed in the basic sense of Ar (eg R ′ ═R ³ or heteroaryl) or R ′ may be COOH. Where a suitable functional group is present, for example, when R 'is a carboxylate functional group, further compounds of formula Ia, wherein R3 is -C (O) NR4R5, are O-[(ethoxycarbonyl) It can be prepared by forming an amide bond with a binder such as -cyanomethyleneamino] -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TOTU).

Compounds of formula (X) can be prepared by palladium-catalyzed Suzuki linkages of aromatic boronic or boric acid esters with intermediates of formula (VI) (Scheme 3). The preparation of compounds of formula X can also be carried out by palladium catalyzed Suzuki bonds (e.g. with palladium dichloride 1,2'-bis (diphenyl-phosphino) ferrocene as catalyst and potassium carbonate as base in dimethylformamide). The intermediate of formula (VII) and the aromatic halide (for example Br-Ar—R ″; R ″ in this case may be initiated in this case, for example, may be hydrogen, —CHO or —COOH) (Scheme 3 ).

If R "= CHO,

NaCNBH ₃ or MP triacetoxyborohydride, HNR4R5

or

NaBH ₄

or

1. NaCNBH ₃ , NH ₄ OAc. 2. R6COCl or R6SO2Cl, pyridine

When R "= COOH,

HNR (3) R (4), TFFH or PPA

Removal of the methyl group from the compound of formula X (eg, with trimethylchlorosilane in acetonitrile and potassium iodide) gives tetrahydroisoquinolinone of formula XI. Compounds of formula (Ib), wherein R 3 is -CH 2 NR 4 R 5 can be prepared by using compounds of formula (XI) wherein R ″ is -CHO, which is reacted by reductive amination with amine NR 4 R 5. It is possible to use reducing agents such as cyanoborohydride or solid phase-bonded triacetoxyborohydride.

Compounds of formula (Ib), wherein R 3 is -CH ₂ OH, are prepared, for example, by compounds of formula (XI) wherein R "is -CHO, which is reacted by reduction with sodium borohydride. .

Compounds of formula (Ib) wherein R 3 is -CH ₂ NHC (O) R 6 or -CH ₂ NHSO ₂ R 6 are subjected to reductive amination with ammonium acetate and the aminomethyl compound thus obtained is subjected to a suitable acid chloride or acid Or by combining with sulfonyl chloride.

Compounds of formula (Ib), wherein R 3 is —C (O) NR 4 R 5, are prepared by compounds of formula (XI) wherein R ″ is —COOH in combination with amine HNR 4 R 5. In this case, carbodiimide, TFFH Or it is possible to use various suitable condensing agents such as phosphoric anhydride (eg PPA).

Compounds of formula (Ib), wherein R 3 is -CHNOR 9, are prepared by compounds of formula (XI) wherein R ″ is -CHO, which reacts to form the hydroxyamine R ₉ ONH ₂ amine.

Compounds of formula (Ib), wherein R 3 is —SO ₂ NR ₄ R 5, are compounds of formula (XI) which are converted to the corresponding sulfochlorides by chlorosulfonation (eg, by chlorosulfonic acid and phosphorus pentachloride in chloroform) , R ″ is H), and sulfochloride reacts with amine HNR 4 R 5.

Compound of formula (Ib), wherein R 3 is -C (O) R 6, is lithiated and reacts with Weinreb amide R 5 C (O) NMe (OMe) to provide the desired compound, wherein , R ″ is H.

A compound of formula (Ib) wherein R 3 is —CH (OH) R 7 is prepared by a lithium compound of formula XI where R ″ is H and reacts with anhydride R 7 CHO.

Compounds of formula (Ib) wherein R 3 is -NHSO ₂ R 6 are prepared by compounds of formula XI wherein R "is -NH ₂ , which reacts with sulfonyl chloride R ₆ SO ₂ Cl in the presence of a base.

Compounds of formula (Ib), wherein R 3 is -NHC (O) R 6) are compounds of formula (XI) wherein R ″ is -NH ₂ in the presence of a base, which reacts with a suitable acid chloride or a suitable acid in the presence of a condensing agent It is prepared by using.

Compounds of formula (Ib), wherein R ₃ is-(C ₂ -C ₃ -alkyl) -NR 4 R 5, use a compound of formula (XI) wherein R ″ is -CHO, which reacts with a suitable Wittig reagent And by subsequent removal of the protecting group and reductive amination of the anhydride with a suitable amine therefrom The Wittich reagent is preferably Ph ₃ P = CHOR.

A compound of formula (Ib) wherein R ₃ is-(C ₂ -C ₃ -alkyl) -NHC (O) R 6 or-(C ₂ -C ₃ -alkyl) -NHSO ₂ R 6) is reacted with a suitable Wittig reagent. Prepared by using a compound of formula XI, wherein R ″ is -CHO, and subsequently removing the protecting group and reductively amination of the aldehyde with ammonium acetate to provide an amine. Such amines are present in the presence of a base. Reaction with suitable acid chloride R 6 C (O) Cl or suitable sulfonyl chloride R ₆ SO ₂ Cl gives the abovementioned compounds.

In all processes, it may be appropriate for the functional groups in the molecule to be temporarily protected in certain reaction protocols. Such protection groups are familiar to those skilled in the art. The selection of protection groups for the groups under consideration and their introduction and removal methods are described in the literature and can be introduced in each case without difficulty if necessary. The invention also relates to the pharmaceutical or pharmacological use of the compounds of formula (I). With respect to the definitions of the substituents X, Ar, R ¹ and R ² (and the definitions of other substituents defined via the substituents mentioned above), reference is made to the statements concerning these compounds.

The pharmaceutical use of the compounds of formula (I) in which one, at least one or all of the abovementioned substituents have the preferred, more preferred, more preferred, very more preferred or particularly preferred meanings mentioned above and includes all combinations with each other One aspect of the present invention.

Compounds of formula (I) are PARP inhibitors and are therefore suitable for the treatment of diseases which progress or are invented in connection with PARP.

Examples of diseases that can be treated with the compounds of the present invention include tissue damage resulting from cell death due to cell damage or necrosis or apoptosis, neuronal interstitial tissue damage or abnormalities, cerebral ischemia, brain trauma, stroke, reperfusion injury, schizophrenia and degenerative Neurological diseases, vascular stroke, cardiovascular abnormalities, myocardial infarction, myocardial ischemia, experimental allergic encephalomyelitis (EAE), multiple sclerosis (MS), ischemia associated with heart surgery, macular degeneration with age, arthritis, atherosclerosis, cancer, aging It includes degenerative diseases of skeletal muscle, diabetes mellitus and diabetic myocardial infarction.

The compounds of the present invention are preferably used for the treatment of diseases caused by ischemia or reperfusion injury. The disease that can be treated is more preferably selected from the group consisting of cerebral ischemia, reperfusion injury, cardiovascular abnormalities, myocardial infarction, myocardial ischemia and ischemia associated with cardiac surgery. The compounds of the present invention can be used in particular for the treatment of myocardial infarction.

The treatment also includes prophylaxis, therapy or treatment of the aforementioned diseases.

All references herein to “compounds of Formula I” refer to compounds of Formula I, their salts, solvates, and physiologically functional derivatives as described herein.

The compounds of formula (I) can be administered to animals and humans, preferably mammals and humans, particularly preferably humans. The compounds of formula (I) can be administered in this regard as the medicaments themselves, in admixture with each other, in admixture with other medicaments or in the form of pharmaceutical compositions. As a result, the use of a compound of formula (I) for the preparation of one or more drugs for the prophylaxis and / or treatment of the abovementioned diseases, pharmaceutical compositions comprising an effective amount of at least one compound of the formula (I) and the prevention of the abovementioned diseases And / or pharmaceutical compositions comprising an effective amount of one or more compounds of formula (I) for treatment are likewise aspects of the invention.

The content of a compound of formula (I) necessary to achieve the desired biological effect depends on a number of factors, for example the particular compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dosage per kg of body weight per day is generally from 0.3 to 100 mg (typically from 3 to 50 mg), for example from 3 to 10 mg / kg / day. Intravenous dosages can be, for example, 0.3 to 1.0 mg / kg, which may suitably be administered at an infusion of 10 to 100 ng per minute per kg. Suitable dosage solutions for this purpose may include, for example, 0.1 ng to 10 mg, typically 1 ng to 10 mg per milliliter. A single dosage may, for example, comprise 1 mg to 10 g of active ingredient. Thus, the ampoules for infusion may, for example, comprise 1 to 100 mg, and for example, orally administrable single dosage forms such as tablets or capsules may be, for example, 1.0 to 1000 mg, generally 10 to 600 mg. For pharmaceutically acceptable salts, the above-mentioned weight data refers to the weight of the free compound from which the salt is derived. For the prophylaxis or therapy of the above-mentioned diseases, it is possible to use the compounds of the formula (I) as the compounds themselves, but they are preferably present with an acceptable carrier in the form of a pharmaceutical composition. Of course, the carrier must be acceptable in view of being compatible with the other ingredients of the composition and not (physiologically acceptable) that is not harmful to the health of the patient. The carrier may be solid or liquid or both, and is preferably prepared as a compound as a tablet, which may comprise a single dosage form, for example, 0.05 to 95% by weight of the active ingredient. Additional pharmaceutically active substances may likewise be present and further comprise compounds of formula (I). The pharmaceutical composition of the present invention may be prepared by one of the known pharmaceutical methods, which consists essentially of mixing the components with a pharmaceutically acceptable carrier and / or adjuvant.

In addition to one or more compounds of formula (I) and one or more carriers, the pharmaceutical compositions of the invention may also comprise an adjuvant. Examples of suitable auxiliaries or additives are fillers, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavors, fragrances, thickeners, diluents, buffers, solvents, solubilizers, storage effects to be achieved. Reagents, salts that alter osmotic pressure, coatings or antioxidants.

The pharmaceutical composition of the present invention is, for example, pills, tablets, pill, swallowable tablets, granules, capsules, hard or soft gelatin capsules, aqueous solutions, alcoholic solutions, oily solutions, syrups, emulsions, Suspensions, suppositories, pastilles, solutions for injection or infusion, ointments, tinctures, creams, lotions, powders, sprays, transdermal therapeutic systems, nasal sprays, aerosols, aerosol mixtures, microcapsules, implants It may be in the form of a rod or a patch.

The pharmaceutical compositions of the present invention are suitable for oral, rectal, topical, mouth (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, but the most suitable mode of administration is In each case it depends on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case. Coated formulations and coated sustained release formulations are also within the scope of the present invention. Acidic and gastric juice resistant formulations are particularly preferred. Coatings suitable for gastric juice resistance include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl-methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical compounds suitable for oral administration are, for example, in the form of discrete units such as capsules, cachets, swallowable tablets or tablets, which are in the form of powders (gelatin capsules or sachets) or granules respectively, aqueous Or as a solution or suspension in a non-aqueous liquid, or in the form of an oil-in-water or oil-in-water emulsion. Such compositions may be prepared by any suitable pharmaceutical method comprising contacting the active ingredient with the carrier (which may consist of one or more additional ingredients), as already mentioned. The composition is generally produced by homogeneous and homogeneous mixing of the active ingredient with a liquid and / or finely divided solid carrier, which then optionally shapes the product. Thus, for example, tablets may be made by compression or molding together with powders or granules of the compound, optionally with one or more additional ingredients. The compressed tablets may be mixed in a suitable machine, for example in a free-flowing form such as powder or granules, optionally with a binder, lubricant, inert diluent and / or one (or more) surface-active / dispersant It can manufacture by tableting. Molded tablets can be prepared by molding in a suitable machine a compound that is in powder form and wetted with an inert liquid diluent. Examples of suitable diluents are starch, cellulose, sucrose, lactose or silica gel. The pharmaceutical composition of the present invention may further comprise a material which is not a diluent, for example one or more lubricants such as magnesium stearate or talc, colorants, coatings (ring agents) or lacquers.

Pharmaceutical compositions suitable for oral (sublingual) administration include swallowable tablets containing the compound of formula (I) together with conventional sucrose and gum arabic or tragacanth and gelatin and glycerol or sucrose and arabian Sachets comprising the compound in an inert base such as rubber.

Pharmaceutical compositions suitable for parenteral administration preferably comprise a sterile aqueous preparation of the compound of formula (I), which is preferably blood and isotonic solution of the desired receptor. Such preparations are preferably administered intravenously, but administration can be by subcutaneous, intramuscular or intradermal injection. Such formulations can preferably be prepared by mixing the compound with water, sterilizing the resulting solution and turning into blood and isotonic solution. Injectable compositions of the invention generally comprise from 0.1 to 5% by weight of active compound.

Sterilizing compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Solvents or vehicles that can be used are water, propylene, glycol, polyethylene glycol and vegetable oils, in particular olive oil, injectable organic esters such as ethyl oleate or other suitable organic solvents. Such compositions may also comprise auxiliaries, in particular wetting agents, reagents for controlling isotonicity, emulsifiers, dispersants and stabilizers. Sterilization can be performed by several methods, for example, aseptic filtration, introduction of the sterilant into the composition, radiation or heating. The compositions can also be prepared in the form of sterile solid compositions which, in use, are dissolved in sterile water or another sterile infusion medium.

Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. It can be prepared by mixing a compound of formula (I) with one or more conventional solid carriers, such as cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers that can be used are petrolatum, lanolin, polyethylene glycol, alcohols and combinations of two or more of these materials. The active ingredient is generally present at a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%.

Percutaneous administration is also possible. Pharmaceutical compositions suitable for dermal penetration may be in the form of a single patch suitable for long term contact with the epidermis of a patient. Such patches suitably contain the active ingredient dissolved and / or dispersed in the adhesive or dispersed in the polymer, in a further buffered aqueous solution. Suitable active ingredient concentrations are about 1 to 35%, preferably about 3 to 15%. It is particularly possible for the active ingredient to be released by electrophoresis or iontophoresis, as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).

The present invention relates to intermediates of the compounds of formula (I). Intermediates of formula (XI) obtainable by the process described above are also an aspect of the present invention. Intermediates of formula (XI) are particularly important when the bond (X) in the compound of formula (I) is a single bond and the substituent Ar is at least monosubstituted by R 3.

In the above formula (XI),

R 1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF ₃ , or hydroxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms,

R2 is hydrogen, fluorine, -CN, hydroxy, methoxy, -OCF ₃ , -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , or hydroxy Oxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms,

R8 is C ₁ -C ₈ -alkoxy, -O-phenyl, C ₁ -C ₃ -alkyl, -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ or phenyl and the phenyl moiety is again fluorine, chlorine, bromine, oxo, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, aryl, heteroaryl, -NHC (O) (C ₁ -C ₃ -alkyl ), -COOH, hydroxy, C ₁ -C ₃ - alkyl, C ₁ - C ₃ - _{alkoxy, -SO 2 NH 2, -SO 2} NH (C 1 -C 3 - alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , At least monosubstituted by -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C ₁ -C ₃ -alkyl) ₂ ,

Ar is aryl or heteroaryl, and such aryl or heteroaryl is fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NH ₂ , -NHC (O ) (C ₁ -C ₆ -alkyl), hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -CH ₂ -CH ₂ -CH ₂ , -CH ₂ -OC (O)-, -CH ₂ -C (O) -O-, -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH ₂ C (O) -NH- , -NH (C ₁ -C ₆ -alkyl), -N (C ₁ -C ₆ -alkyl) ₂ , -SO ₂ (C ₁ -C ₆ -alkyl), heterocyclyl, heteroaryl and aryl Optionally substituted by one or more substituents selected from among which heterocyclyl, aryl and heteroaryl are, in turn, substituted with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, fluorine, chlorine, bromine, trifluoro At least monosubstituted by methyl, trifluoromethoxy or OH,

R "is -COOH, -CHO or -SO ₂ Cl,

Heteroaryl is a 5 to 10 membered aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S,

Heterocyclyl is a 5-10 membered non-aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S,

Aryl is a 5-10 membered aromatic monocycle or bicycle.

In preferred compounds of formula (XI),

R 1 is hydrogen or C ₁ -C ₃ -alkyl,

R2 is hydrogen,

Ar is phenyl, thienyl, furanyl or pyridinyl, and such phenyl, thienyl, furanyl or pyridinyl is fluorine, chlorine, -CF ₃ , -OCF ₃ , -C (O) (C ₁ -C _3- Alkyl), -NH ₂ , -NHC (O) (C ₁ -C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -OC (O)-, -CH ₂ -C (O) -O-, -CH ₂ NH-C (O)-, -CH ₂ N (CH ₃ ) -C (O)-, From -CH ₂ -C (O) -NH-, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ and -NO ₂ (C ₁ -C ₃ -alkyl) Optionally substituted by one or more substituents selected,

R "is -COOH, -CHO or -SO ₂ Cl,

In particularly preferred compounds of formula (XI),

R 1 is hydrogen or C ₁ -C ₃ -alkyl,

R2 is hydrogen,

Ar is phenyl, furanyl, thienyl or pyridinyl, and the R ″ and tetrahydroquinolinone moieties are in meta positions relative to each other,

R "is -CHO or -COOH.

Test

List of abbreviations

^t Bu tert-butyl

dba dibenzylidene acetone

DCM dichloromethane

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylaminopyridine

D6-DMSO Deuterated Dimethyl Sulfoxide

eq. Molar equivalent

MP Highly Crosslinked Macroporous Polystyrene

NBS N-bromosuccinimide

PdCl ₂ (dppf) 1,1'-bis (diphenylphosphino) ferrocenepalladium (II) chloride

PPA Propanephosphonic Acid Anhydride

RF reflux

RT room temperature

RP-HPLC Reversed Phase High Performance Chromatography

SCX cation exchanger ('strong cation exchanger')

TFFH tetramethylfluoroaminedinium hexafluorophosphate

TFA trifluoroacetic acid

TFH tetrahydrofuran

TMS trimethylsilyl

TOTU O-[(ethoxycarbonyl) cyanomethyleneamino] -N, N, N ', N'-

                Tetramethyluronium Tetrafluoroborate

Synthesis of Phthalimide of Formula (II)

The synthesis method of Scheme 1 is demonstrated by compound 1.

Ethyl 2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) propionate (Compound 1)

In an open round bottom flask at 120 ° C., 20.87 g (0.141 mol) of phthalic anhydride and 16.5 g (0.141 mol) of ethyl aminopropionate are added together. 300 ml of cyclohexane are added and the mixture is heated to reflux. The heated cyclohexane solution is separated by decanting from the residual oil and concentrated completely. A viscous oil that slowly solidifies is obtained (31 g, 89% yield).

MS: m / z = 248 (M + 1)

1 H-NMR (CDCl 3): δ = 7.87 (2H, m); 7.74 (2H, m); 4.96 (1H, q, J = 7.3 Hz); 4.21 (2H, m); 1.70 (3H, doublet, J = 7.3 Hz); 1.24 (3H, t, J = 7.1 Hz).

4-hydroxy-3-methyl-2H-isoquinolin-1-one (compound 2)

31.8 g (129 mmol) of Compound 1 are dissolved in 22 ml of pure methanol, 15.2 ml of 28% sodium methanolate solution (257 mmol) is added, and heated to reflux for 3 hours. The solution is concentrated and concentrated aqueous ammonia solution is added to the residue. After 2 hours, the solid is filtered off with suction and washed with cooling water. 14.1 g (63% yield) of a white solid are obtained.

MS: m / z = 176 (M + 1)

1 H-NMR (CD3 OD): d = 8.21 (1H, d, J = 8.8 Hz); 8.14 (1H, doublet, J = 8.3 Hz); 7.65 (1 H, m); 7.38 (1 H, m); 2.30 (3H, s).

3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Compound 4)

8.45 g (53 mmol) of 3-methyl-2H-isoquinolin-1-one is dissolved in 80 ml of glacial acetic acid, and after addition of 168 mg (0.74 mmol) of platinum (V), hydrogenated at 5 bar at room temperature for 8 hours. The suspension is filtered, concentrated and the residue is recrystallized from methanol. 7.15 g (83%) of a colorless oil are obtained.

MS: m / z = 160 (M + 1)

1 H-NMR (CDCl 23): d 10.55 (1H, s); 8.37 (1H, doublet, J = 8.1 Hz); 7.62 (1 H, m); 7.43 (2H, m); 6.31 (1 H, s); 2.37 (3 H, s).

5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Compound 5)

60 g (413 mmol) of 2H-isoquinolin-1-one (isocarbostyryl) is dissolved in 1 L of glacial acetic acid, and after addition of 2.3 OH (10 mmol) of platinum (IV) oxide, hydrogenation is carried out at room temperature under 3 bar until conversion is complete. . This changes the catalyst after 3 days and an additional 5 days. The suspension is filtered, concentrated and concentrated again after toluene addition. The crude product is recrystallized from 1.6 liters of water. The long needles are filtered off, the mother liquor is concentrated, dried and separated on silica gel. 36.8 g (60%) of a colorless oil are obtained.

MS: m / z = 164 (M + 1)

1 H-NMR (CDCl 3): d 10.7 (1 H, s); 5.78 (1 H, s); 2.50 (4H, m); 2.22 (3H, s); 1.73 (4 H, m).

4-Bromo-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Compound 6)

7.15 g (43.8 mmol) of compound 4 are dissolved in 50 ml of methanol at 0 ° C. and a total of 7.4 g (41.6 mmol) of N-bromosuccinimide is added in portions. After 3 hours of reaction at 0 ° C., the residue from filtration by suction is washed with a small amount of cold water and dichloromethane. 8.9 g (84% yield) of colorless bromide are obtained.

MS: m / z = 150 (M + 1)

1 H-NMR (D 6 -DMSO): d = 11.20 (1 H, s); 7.08 (1H, doublet, J = 6.8 Hz); 5.90 (1H, doublet, J = 6.8 Hz); 2.47 (2H, m); 2.30 (2H, m); 1.64 (4 H, m).

4-Bromo-5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Compound 7)

32.4 g (217 mmol) of tetrahydroisoquinolinone (Compound 5) were dissolved in 300 ml of chloroform at 5 ° C, and 11.2 ml (34.7 g, 217 mmol) of bromine dissolved in 150 ml of chloroform was added dropwise over 1 hour. The mixture is stirred for an additional 1 hour while cooling on ice, neutralized with 150 ml of saturated NaHCO 3 solution and filtered by suction. The organic phase of the filtrate is extracted with dichloromethane and concentrated. The residue is mixed with ethyl acetate, filtered by suction and dried in a vacuum drying oven at 45 ° C. with the first residue. 47.7 g (96%) of colorless bromide are obtained.

MS: m / z = 242/244 (M + 1)

1 H-NMR (CDCl 3): d = 12.4 (1 H, s); 2.57 (4H, m); 2.43 (3H, s); 1.75 (4 H, m).

4-Bromo-1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinoline (Compound 8)

8.9 g (36.mmol) of 4-bromo-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one is dissolved in 200 ml of chloroform and 13.7 g of silver carbonate (I). (49.6 mmol) and 16.2 mL (36.5 g, 257 mmol) of iodomethyl were added and then stirred at 50 ° C. for 3 hours. After an additional 24 hours at room temperature, the suspension is filtered through celite, concentrated and chromatographed with n-heptane with 2% ethyl acetate on silica gel. A colorless oil (7.8 g, 83% yield) is obtained.

MS: m / z = 228/230 (M + 1)

1 H-NMR (CDCl 3): d = 9.50 (1 H, s); 8.03 (1 H, s); 2.28 (2H, m); 2.18 (2H, m); 1.85 (4 H, m).

4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline (Compound 9)

47.7 g (209 mmol) of 4-bromo-5,6,7,8-tetrahydro-2H-isoquinolin-1-one are dissolved in 1 L of chloroform, 77.8 g (282 mmol) of silver carbonate (I) and iodomethyl 53.5 mL (118.7 g, 836 mmol) is added and then stirred at 50 ° C. for 3 hours. After cooling, the suspension is filtered through celite, concentrated and chromatographed with n-heptane with 2% ethyl acetate on silica gel. Obtains a colorless oil (42.5 g, 84% yield).

MS: m / z = 256/258 (M + 1)

1 H-NMR (CDCl 3): d = 3.89 (3H, s), 2.65 (2H, m); 2.53 (2H, m); 2.51 (3H, s); 1.75 (4 H, m).

1-methoxy-3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -5,6,7,8-tetrahydro Isoquinoline (Compound 10)

128 mg (0.5 mmol) of bromide, 218 μl (1.64 mmol) of triethylamine, and 83 mg (0.65 mmol) of 4,4,5,5-tetra methyl-1,3,2-dioxaborolane were treated under Dissolve in 2 ml of oxane and finally add 19 mg (0.027 mmol) of PdCl 2 (dppf) and stir the mixture at 90 ° C. for 60 h and stir at microwave at 150 ° C. for an additional 2.5 h. The mixture is diluted with water and ethyl acetate and the organic phase is washed with water, concentrated and purified on silica gel. A white solid (100 mg, 66% yield) is obtained.

MS: m / z = 242/244 (M + 1)

1 H-NMR (CDCl 3): d = 8.03 (1 H, s); 3.90 (3H, s); 2.66 (2H, m); 2.57 (2H, m); 1.78 (4 H, m).

1-methoxy-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -5,6,7,8-tetrahydroisoquinoline (Compound 11)

8.0 g (33 moles) of bromide 9, 14.4 mL (109 mmol) of triethylami and 5.5 g (42.9 mmol) of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane under argon Dissolve in 50 mL of dioxane and finally add 1.28 g (1.75 mmol) of PdCl 2 (dppf) and stir the mixture at 90 ° C. for 18 h. The cold mixture is mixed with water, extracted twice with ethyl acetate, the organic phase is dried, concentrated and chromatographed on silica gel. A white solid (7.75 g, 81% yield) is obtained.

MS: m / z = 304 (M + 1)

1 H-NMR (CDCl 3): d = 4.08 (3H, s); 2.68 (2H, m); 2.58 (3 H, s); 2.52 (2H, m); 1.75 (4 H, m); 1.38 (12 H, s).

General process

One equivalent of bromide (compound 8 or 9), 1.5 equivalents of aniline and 1.4 equivalents of NaOtBu are injected under pure argon to pure toluene (2 mL / mmol). After stirring for 10 minutes at room temperature, 0.05 equivalents of tris (dibenzylideneacetone) dipalladium and 0.2 equivalents of di-tert-butylphosphinobiphenyl are added, and the mixture is heated in a microwave at 150 ° C. (CEM Discover). React for minutes. The reaction mixture is diluted with water and ethyl acetate, the organic phase is separated, concentrated and purified by RP-HPLC. The basic compound is separated as trifluoroacetate.

Ethyl 3- (1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino) benzoate (Compound 12)

580 mg (4.9 mmol) of 95% pure KO ^t Bu is injected into 20 ml of pure toluene. After 3 discharges and ventilation with argon, 4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline 847 mg (3.5 mmol) and ethyl 3-aminobenzoate 868 mg (5.25 mmol) Add). 160 mg (0.175 mmol) of tris (dibenzylidene) dipalladium and 209 mg (0.7 mmol) of di-tert-butylphosphinobiphenyl are heated at 100 ° C. for 3 hours. After inspection, the mixture is concentrated and the residue is separated between H ₂ O and ethyl acetate. The phases are separated and the aqueous phase is extracted three more times. The combined organic phases are washed one or more times with H ₂ O, dried over Na ₂ SO ₄ and concentrated. Further purification is performed by chromatography on silica gel (CH ₂ Cl ₂ / MeOH 99: 1) to give 640 mg of the title compound. Yield: 55%

The next additional compound is prepared according to the general procedure.

Synthesis of Compound of Formula X by Suzuki Bond with Bromides of Formula VI and Boronic Acid of Formula (OH) ₂ B-Ar-R "

General process

One equivalent of bromide (compound 8 or 9), 3.3 equivalents of potassium iodo and 1.2 equivalents of boric acid are introduced under pure argon with pure THF (3 mL / 1 mmol). 0.05 equivalent Pd2dba and 0.1 equivalent tri-tert-butylphosphonium tetrafluoroborate are added and the mixture is stirred at 60 ° C. for 15 hours. After cooling, neutralize with saturated NaHCO 3 solution, extract twice with ethyl acetate, and concentrate the organic phase. The residue is chromatographed on silica gel.

1-methoxy-3-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydroisoquinoline (Compound 30)

20 mg (31% yield) of Compound 30 is obtained from 70 mg of Bromid 8 according to the general procedure.

MS: m / z = 260 (M + 1)

1 H-NMR (CDCl 3): d = 7.37 (1H, doublet of doublets, J = 5.1, 1.1 Hz); 7.09 (1H, doublet of doublets, J = 5.1, 3.4 Hz); 6.79 (1H, doublet of double, 3.4, 1.1 Hz); 3.96 (3H, s); 2.58 (2H, m); 2.40 (2H, m); 2.24 (3H, s); 1.70 (4 H, m).

1-methoxy-3-methyl-4-pyridin-3-yl-5,6,7,8-tetrahydroisoquinoline (Compound 31)

49 mg (49% yield) of compound 31 are obtained from 100 mg of bromide 8 according to the general procedure.

MS: m / z = 260 (M + 1)

5- (1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-yl) furan-2-carbaldehyde (Compound 32)

4.59 mg (100% yield) of Compound 32 is obtained from 4.32 g (17.9 mmol) of Bromid 9 according to the general procedure.

MS: m / z = 258 (M + 1)

5- (1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinolin-4-yl) furan-2-carbaldehyde (Compound 33)

1.86 g (79% yield) of compound 33 are obtained from 2.0 g of bromide 8 according to the general procedure.

MS: m / z = 272 (M + 1)

1 H-NMR (CDCl 3): d = 9.65 (1 H, s); 7.34 (1H, doublet, J = 3.4 Hz); 6.49 (1H, doublet, J = 3.4 Hz); 3.96 (3H, s); 2.57 (2H, m); 2.46 (2H, m); 2.30 (3H, s); 1.71 (4 H, m).

Synthesis of Compound of Formula X by Suzuki Bonding of Boric Acid Ester of Formula VII to Bromid of Formula Br-Ar-R3

This synthesis is shown for the following compounds by way of example.

5- (1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-yl) nicotinic acid (compound 34)

7.75 g (26.8 mmol) of boric acid ester 11, 14.82 g (107.2 mmol) of potassium carbonate and 980 g (1.34 mmol) of PdCl2 (dppf) were injected into 60 ml of pure DMF under argon, and 7 g (34.9 mmol) of 5-bromonicotinic acid Add). The mixture is stirred at 110 ° C. for 18 hours, water is added, and the pH is adjusted to 4 with 2N HCL solution. Two extractions are carried out with DCM and the organic phase is filtered and concentrated. The residue is extracted in 200 ml of DCM, mixed with activated carbon and filtered through celite. The filtrate is concentrated and dried overnight in a vacuum drying oven. 7.4 g (97% yield) of black crystals are obtained.

MS: m / z = 285 (M + 1)

Synthesis of Compounds 35 to 39 (Intermediate) by Deprotection of Methoxy Group

5- (1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl) furan-2-carbaldehyde (Compound 35)

4.59 g (17.8 mmol) of compound 32 is suspended in 60 ml of acetonitrile. 3.26 g (19.6 mmol) of Kl and 2.13 g (19.6 mmol) of trimethylchlorosilane were added and then treated for 6 hours under argon at 60 ° C. The mixture is concentrated completely and the residue is treated with aqueous NaHCO 3 solution. The residue is extracted three times with DCM and the organic phase is dried and concentrated. The residue is dissolved in 100 ml of EtOH and Norit carbon is added. Filtration and concentration are carried out. About 1 g of the title compound is obtained. Additional crude product is separated from the carbon residue by extraction with DCM and purified on silica gel. Total yield: 2.38 g (55%) white solid

MS: m / z = 244 (M + 1)

1 H-NMR (CDCl 3): d = 12.6 (1 H, s); 9.65 (1 H, s); 7.75 (1 H, s); 7.29 (1H, doublet, J = 3.4 Hz); 6.56 (1H, doublet, J = 3.4 Hz); 2.75 (2H, m); 2.62 (2H, m); 2.62 (2H, m); 1.70 (4 H, m).

5- (3-Methyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl) furan-2-carbaldehyde (Compound 38)

172 mg (27% yield) of the title compound are obtained similar to compound 35 from 660 mg (2.43 mmol) of compound 33 after purification by RP-HPLC.

MS: m / z = 258 (M + 1)

1 H-NMR (CDCl 3): d = 11.4 (1 H, br s); 9.65 (1 H, s); 7.35 (1H, doublet, J = 3.4 Hz); 6.58 (1H, doublet, J = 3.4 Hz); 2.61 (2 H, m); 2.43 (2H, m); 2.35 (3 H, s); 1.72 (4H, m).

5- (1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl) nicotinic acid (Compound 37)

3.1 g (28.5 mmol) of compound 34 are suspended in 100 ml of acetonitrile. 4.73 g (28.5 mmol) of Kl and 3.1 g (28.5 mmol) of trimethylchlorosilane are added and then heated at 80 ° C. under argon for 2 hours. The mixture is cooled to rt, concentrated completely and extracted in 5: 1 ethyl acetate / MeOH. The precipitate (4.78 g) is filtered off with suction and dried overnight in a vacuum drying oven at 45 ° C. The mother liquor is concentrated and the filtrate is purified on silica gel. Overall yield: 5.64 g (81%) of a light off-brown solid

MS: m / z = 271 (M + 1)

1 H-NMR (D 6 -DMSO): d = 11.7 (1 H, br s); 9.03 (1H, doublet, J = 2.0 Hz); 8.74 (1H, doublet, J = 2.2 Hz); 8.12 (1H, t, J = 2.2 Hz); 2.41 (2H, m); 2.32 (2H, m); 1.63 (4 H, m).

Ethyl 3- (1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino) benzoate (Compound 38)

560 mg (1.7 mmol) of ethyl 3- (1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino) benzoate (Compound 12) were dissolved in 30 ml of chloroform, and at room temperature, 413 mg (2.1 mmol) of trimethylsilyl iodide are added. The mixture is heated to reflux until complete ring conversion is reached by LCMS. Additional trimethylsilyl iodine is added if necessary. For inspection, the mixture is washed twice with H ₂ O, dried over Na ₂ SO ₄ and concentrated. Chromatography on silica gel (CH ₂ Cl ₂ / MeOH 95: 5) gave 216 mg of the title compound. Yield: 40%

MS: m / z = 313 (M + 1)

3- (1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino) benzoic acid (Compound 39)

180 mg (0.58 mmol) of ethyl 3- (1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino) benzoate (Compound 38) were injected into 3 ml of ethanol, and 2N at room temperature. Add 3 ml of KOH. After 2 hours, the solvent is removed in vacuo and the residue is taken up in 5 ml of H ₂ O and oxidized with 2N HCl. The resulting precipitate is filtered off with suction and dried. Yield: 123 mg (75%).

MS: m / z = 285 (M + 1)

Synthesis of Tetrahydro-2H-isoquinolinone of Formula (I) by Deprotection of 1-methoxy-5,6,7,8-tetrahydroisoquinoline of Formula (VIII) and (X)

General process

2 equivalents of iodopotassium and 2 equivalents of trimethylchlorosilane in 1-methoxy-5,6,7,8-tetrahydroisoquinoline of formula (VIII) and (X) in anhydrous athenitrile (3-5 mL / mmol) under argon To 2 equivalents, the cloudy mixture is heated at 60 to 80 ° C. for 1 to 3 hours. The mixture is cooled to room temperature and concentrated. The crude product is purified by RP-HPLC and the basic compound is isolated as trifluoroacetate.

The following example is synthesized according to the general protocol.

4- (5-hydroxymethylfuran-2-yl) -3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Example 9)

The title compound is used in the reductive amination of 5- (3-methyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl) furan-2-carbaldehyde (Compound 36). Obtained as a by-product and separated by RP-HPLC.

MS: m / z = 260 (M + 1)

1 H-NMR (D 6 -DMSO): d = 11.52 (1 H, br s); 6.33 (1H, doublet, J = 2.9 Hz); 6.27 (1H, doublet, J = 2.9 Hz); 4.38 (2H, s); 2.33 (2H, m); 2.23 (2H, m); 2.03 (3H, s); 1.59 (4 H, m).

The following Examples 10-19 are prepared according to Examples 1-8.

Synthesis of Examples 20 to 24 by Combination of Compound 39 and an Amine

General process

38 mg (0.13 mmol) of 3- (1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino) benzoic acid were injected into 2 ml of DMF, and 20 µl of triethylamine at room temperature 0.15 mmol) is added. At 0 ° C., TOTU 52 mg (0.16 mmol) is added and the mixture is stirred at 0 ° C. for 15 minutes. After an additional 30 minutes at room temperature, the solution is added to a second solution of amine (0.15 mmol) and 20 μl (0.15 mmol) triethylamine, respectively, in 2 ml of DMF and complete conversion at room temperature is found by LCMS. Stir until. For inspection, the solvent is removed and purification is carried out on silica gel.

The following compounds are prepared by the general procedure described.

N-butyl-3- (1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino) benzamide (Example 20)

Yield 31% after silica gel chromatography (CH ₂ Cl ₂ / MeOH 95: 5).

R _t = 1.166 min ¹⁾ ; MS (M + H ⁺ ) = 340.15; 500 MHz ¹ H-NMR (DMSOd ₆ ) [ppm]: 11.30, 1H, s, NH; 7.20-7.00, m, 5H, 4 x aromat. H, NH; 6.62, dd, 1 H, aromat. H; 3.20, m, 2H, CH ₂ ; 2.33 m, 4H, 2 x CH ₂ ; 1.62, m, 2H, CH ₂ ; 1.58, m, 2H, CH ₂ ; 1.46, m, 2H, CH ₂ , 1.30, m, 2H, CH ₂ ; 0.88, t, 3 H, CH ₃ .

4- [3- (pyrrolidine-1-carbonyl) phenylamino] -5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Example 21)

Yield 74% after silica gel chromatography (CH ₂ Cl ₂ / MeOH 95: 5).

R _t = 1.052 min ¹⁾ ; MS (M + H ⁺ ) = 338.15; 500 MHz ¹ H-NMR (DMSOd ₆ ) [ppm]: 11.30, 1H, s, NH; 7.22-7.05, m, 3H, 2 x aromat. H, NH; 6.71, dd, 1 H, aromat. H; 6.63-6.55, m, 2H, aromat. H; 3.08, m, 4H, 2 x CH ₂ ; 2.33, m, 4H, 2 x CH ₂ ; 1.90-1.73, m, 4H, 2 x CH ₂ ; 1.68-1.52, m, 4H, 2 × CH ₂ .

4- [3- (4-cyclopropylmethylpiperazin-1-carbonyl) phenylamino] -5,6,7,8-tetrahydro-2H-isoquinolin-1-ol (Example 22)

Yield 67% after silica gel chromatography (CH ₂ Cl ₂ / MeOH 95: 5).

R _t = 0.839 min ¹⁾ ; MS (M + H ⁺ ) = 407.25.

3- (1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino) -N- (2-pyridin-3-ylethyl) benzamide (Example 23)

Yield 63% after silica gel chromatography (ethyl acetate / MeOH 10: 1 → 4: 1).

R _t = 1.03 min ¹⁾ ; MS (M + H ⁺ ) = 389.11.

3- (1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino) -N- (2-pyrrolidin-1-ylethyl) benzamide (Example 24 )

Yield 66% after silica gel chromatography (ethyl acetate / MeOH 10: 1 → MeOH).

R _t = 1.05 min ¹⁾ ; MS (M + H ⁺ ) = 381.15.

LCMS  Way:

¹⁾ YMC J'sphere ODS H80 20 × 2, 4 μm;

    0 min 96% H 2 O (0.05% TFA) 2.0 min-95% ACN; 95% ACN to 2.4 minutes;

    4% ACN 2.45 min;

    1 ml / min;

    30 ° C.

²⁾ Col YMC J'sphere 33 × 2, 4 μm;

    Grad ACN + 0.05% TFA: H2O + 0.05% TFA

    5.95 (0 min) to 95: 5 (3.4 min) to 95: 5 (4.4 min);

    1 ml / min;

    30 ° C.

Synthesis of Examples 25-49 by Combination of Compound 37 and an Amine

General process

5- (1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl) -nicotinic acid 54 mg (0.2 mmol), amine 0.24 mmol, 4-DMAP 0.02 mmol, N-methyl 0.8 mmol of morpholine and 0.4 mmol of PPA (50% solution in DMF) are mixed in 3 ml of pure DCM at room temperature and stirred for 18 hours. The mixture is diluted with a small amount of DCM, washed with saturated NaHCO 3 solution, the organic phase is concentrated and the residue is purified by RP-HPLC. The basic compound is separated as trifluoroacetate.

The following examples are prepared according to the general protocol.

4- (5-Aminomethylfuran-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Example 50)

2.18 g (9.0 mmol) of Compound 35 was dissolved in 160 mL of methanol / THF (5/1) together with 844 mg (13.4 mmol) of NaCNBH4 and 55.3 g (717 mmol) of ammonium acetate and reacted at room temperature for 18 hours. The yellow solution is concentrated completely and the residue is chromatographed on ethyl acetate with ethyl acetate / methanol (1/1). Separated compounds that still contain relatively large amounts of salts are subsequently chromatographed by RP-HPLC. 400 mg of the title compound is isolated.

MS: m / z = 245 (M + 1)

Synthesis of Examples 51-79 by Reductive Amination of Compounds 35 and 36 with Amines

General process

5- (3-methyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl) furan-2-carbaldehyde or 5- (1-oxo-1,2, 0.2 mmol of 5,6,7,8-hexahydroisoquinolin-4-yl) furan-2-carbaldehyde and 0.24 mmol of amine were dissolved in 2 ml of THF and after addition of about 0.5 mmol of MP triacetoxyborohydride Vibrate at room temperature for 18 hours. The solution is filtered and the resin is washed twice with 4 ml of THF each, the complete organic phase is concentrated and purified by RP-HPLC. The compound is separated as trifluoroacetate after cooling to dryness.

Synthesis of Examples 80-84 by Acylation of Example 50 with Carboxylic Acids

General process

4- (5-aminomethylfuran-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one was converted to DCM with acid chloride or acid anhydride 0.15 mmol and triethylamine 0.375 mmol. Dissolve in 5 ml and stir at 0 ° C. for 2 hours. The reaction mixture is mixed with water, extracted with DCM, the organic phase is concentrated and purified by RP-HPLC. Example 84 is isolated as trifluoroacetate.

The following compounds are prepared according to the general protocol.

Synthesis of Examples 85-87 by Reaction of Example 50 with Sulfonyl Chloride

General process

4- (5-aminomethylfuran-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one in 5 ml of DCM with 0.18 mmol of sulfonyl chloride and 0.375 mmol of potassium carbonate Dissolve and stir for 18 hours at room temperature. The reaction mixture is mixed with water, extracted with DCM, the organic phase is concentrated and purified by RP-HPLC. Example 85 is separated by trifluoroacetate.

Pharmacological Research

PARP Enzyme Assay

The maximum intermediate inhibitor concentration is determined by culturing the material to be tested with DNA-activated, recombinantly expressed and purified PARP-1 enzyme. In particular, the various concentrates of the test substance were Tris 50 mM, MgCl ₂ 5 mM, DTT 1 mM, NAD 200 μM, Tritium-attached NAD 0.1 mM / ml, DNA 0.1 mg / ml, Histone 0.1 mg / ml, recombinantly expressed human PARP-1 Incubate 50 μl of the reaction solution containing 2 μg / ml of enzyme at room temperature and pH = 8.0 for 1 hour. The reaction is stopped by adding 150 µl of 20% trichloroacetic acid, and the radioactive protein component is precipitated. After 10 minutes of incubation on ice, the identified and insoluble components were separated through a glass fiber filter, washed three times with 20% trichloroacetic acid, and the radioactivity incorporated by the PARP-1 enzyme was determined by radioluminescence. Is measured. Considering the incorporation rate, which is measured as a function of the concentration of the test substance in this method, the maximum intermediate inhibitor concentration (IC ₅₀ ) is the concentration of the test substance that reduces the incorporation rate to the maximum possible median (incubation without inhibitor).

IC-50 was measured for the following compounds by this method.

Analysis of ATP Consumption in Cardiomyocytes

The activity of the test substance in the cells is confirmed by ATP consumption assay. For the same purpose, rat cardiomyocytes (H9c2 cell line) are planted in 96-well plates (40,000 cells per well, RPMl 1640; 10% FCS) and maintained at 37 ° C., 5% CO ₂ for 16 hours. The cells are washed with PBS and incubated for 15 minutes under the same conditions as various concentrates of the test substance in the medium. After addition of 300 μM H ₂ O ₂ , the cells are maintained at 37 ° C., 5% CO ₂ for an additional hour, assayed, and the cell content of ATP is measured by luciferase reaction. The maximum intermediate concentration of the substance (EC50) is measured as the concentration at which the ATP content of the cell reaches half the value that can be measured as the maximum effective concentration of the same substance.

Enzyme Inhibition Assay by Various Substrate Concentrations

The apparent K _i value of the test substance is determined in an enzyme assay using purified human PARP-1 enzyme. In particular, various concentrates of tritium-attached substrate NAD were found to be tris 50 mM, MgCl ₂ 5 mM, DTT 1 mM, NAD 200 μM, tritium-attached NAD 0.1 mM / ml, DNA 0.1 mg / ml, histone 0.1 mg / ml, recombinantly expressed. 50 μl of the reaction solution containing 2 μg / ml of human PARP-1 enzyme was incubated for 10 minutes at the same concentration of test substance at room temperature and pH = 8.0. The reaction is stopped by adding 150 μl of 20% trichloroacetic acid and the radioactive protein component precipitates. After 10 minutes of incubation on ice, the insoluble components identified are separated through a glass fiber filter, washed three times with 20% trichloroacetic acid, and then radioactivity incorporated by PARP-1 enzyme is measured by radioluminescence. . Measurement of the incorporation rate, measured as a function of the concentration of substrate NAD in this method, gives an apparent K _i value according to the Michaelis-Menten kinetics, and the process of inhibition is purely competitive.

EC-50 values and apparent K _i are determined for all of the following selected compounds in the method.

Claims (17)

A compound of formula (I) or a physiologically acceptable salt thereof. Formula I

In Formula I above, X is a single bond, O, S, NH or N (C ₁ -C ₃ -alkyl), R 1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF ₃ , or hydroxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms, R2 is hydrogen, fluorine, -CN, hydroxy, methoxy, -OCF ₃ , -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , or hydroxy Oxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms, Ar is unsubstituted or at least monosubstituted aryl or heteroaryl, wherein the substituents are fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NH ₂ , -NHC (O) (C ₁ -C ₆ -alkyl), hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -CH ₂ -CH ₂ -CH _2- , -CH _2- OC (O)-, -CH ₂ -C (O) -O-, -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH _2- C (O) —NH—, —NH (C ₁ -C ₆ -alkyl), -N (C ₁ -C ₆ -alkyl) ₂ , -SO ₂ (C ₁ -C ₆ -alkyl), heterocyclyl, Heteroaryl, aryl and R 3, and heterocyclyl, aryl and heteroaryl of these substituents are in turn C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, fluorine, chlorine, bromine, trifluor At least monosubstituted by romoxy, trifluoromethoxy or OH, R3 is-(C ₁ -C ₃ -alkyl) -NR4R5, -SO ₂ NR4R5, -C (O) NR4R5, -C (H) = N-OR9, -C (O) R6, -NHC (O) R6 ,-(C ₁ -C ₃ -alkyl) -NHC (O) R 6, -NHSO ₂ R 6,-(C ₁ -C ₃ -alkyl) -NHSO ₂ R 6 or -CH (OH) R 7, R4 and R5 are independently of each other hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, heteroaryl and heterocyclyl Selected from the group consisting of aryl, heteroaryl, heterocyclyl, -O-aryl, fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NHC (O) (C ₁ -C ₃ -alkyl), -NH ₂ , hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl ), -N (C ₁ -C ₃ -alkyl) ₂ , -NH-aryl, -NH-heteroaryl, -NH-C (O) -heteroaryl, -SO ₂ NH ₂ , -SO ₂ (C _1- C ₃ -alkyl) and -NH-SO ₂ (C ₁ -C ₃ -alkyl), wherein the aryl, heteroaryl and heterocyclyl moieties of these substituents are again fluorine, chlorine, bromine, oxo,- _{CF 3, -OCF 3, -NO 2} , -CN, aryl, _{heteroaryl, -NHC (O) (C 1} -C 3 - alkyl), -COOH, hydroxy, C ₁ -C ₃ - Al Kiel, C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C At least monosubstituted by _1- C ₃ -alkyl) ₂ , or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted heterocyclyl, wherein the substituents are aryl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, bromine,- _{CF 3, -OCF 3, -NO 2} , -CN, -C (O) R8, -NHC (O) (C 1 -C 3 - alkyl), -NH _2, hydroxy, C ₁ -C ₃ - alkyl , C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C _3- Alkyl) and -NH-SO ₂ (C ₁ -C ₃ -alkyl), aryl, heterocyclyl and heteroaryl of these substituents are again fluorine, chlorine, bromine, hydroxy, C ₁ -C ₃ - it may be at least monosubstituted with an alkoxy, -alkyl or C ₁ -C ₃ R 6 is unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl, heteroaryl or heterocyclyl, wherein the substituents are fluorine, chlorine, bromine, aryl, heterocyclyl, heteroaryl, —CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NHC (O) (C ₁ -C ₃ -alkyl), -NH ₂ , hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -O-heteroaryl, -O-aryl, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and -NH-SO ₂ (C ₁ -C ₃ -alkyl) and the aryl, heterocyclyl and heteroaryl moieties of these substituents are again fluorine, chlorine At least monosubstituted by, bromine, hydroxy, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy, R 7 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl and heteroaryl, wherein the substituents are fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R8, -NHC (O) (C ₁ -C ₃ -alkyl), -NH ₂ , hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and -NH-SO ₂ ( C ₁ -C ₃ -alkyl), R8 is C ₁ -C ₃ -alkoxy, -O-phenyl, C ₁ -C ₃ -alkyl, -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ or phenyl, wherein the phenyl moiety is again fluorine, chlorine, bromine, oxo, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, aryl, heteroaryl, -NHC (O) (C ₁ -C ₃ -Alkyl), -COOH, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) At least monosubstituted by ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C ₁ -C ₃ -alkyl) ₂ There is, R 9 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl and phenyl, wherein the substituents are fluorine, chlorine, bromine, aryl, heterocyclyl, heteroaryl, —CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NHC (O) (C ₁ -C ₃ -alkyl), C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ NH ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and -NH-SO ₂ ( C ₁ -C ₃ -alkyl), and the aryl, heterocyclyl and heteroaryl of these substituents are again converted into fluorine, chlorine, bromine, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy At least monosubstituted by Heteroaryl is a 5 to 10 membered aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S, Aryl is a 5-10 membered aromatic monocycle or bicycle, Heterocyclyl is a 5-10 membered non-aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S, When X is a single bond, Ar is not unsubstituted phenyl. The method of claim 1, X is a single bond, NH or N (C ₁ -C ₃ -alkyl), R 1 is hydrogen or C ₁ -C ₃ -alkyl optionally substituted by hydroxy, chlorine, methoxy or 1, 2 or 3 fluorine atoms, R2 is hydrogen, fluorine, -OCF ₃ , hydroxy, methoxy, -NH ₂ or C ₁ -C ₃ -alkyl, Ar is unsubstituted or at least monosubstituted phenyl or heteroaryl, wherein the substituents are fluorine, chlorine, -CF ₃ , -OCF ₃ , C (O) (C ₁ -C ₃ -alkyl), -NH ₂ ,- NHC (O) (C ₁ -C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -CH ₂ -CH ₂ -CH _2- , -CH ₂ -OC ( O)-, -CH ₂ -C (O) -O-, -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH ₂ -C ( O) -NH-, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), heterocyclyl, heteroaryl And R 3, wherein heterocyclyl and heteroaryl of these substituents are again C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluorome At least monosubstituted by oxy or OH, R3 is -CH ₂ -NR4R5, -SO ₂ NR4R5, -C (O) NR4R5, -CH ₂ NHC (O) R6, -CH ₂ -NHSO ₂ R6 or -CH (OH) R7, R 4 and R 5 independently of one another are preferably a group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, indanyl, heterocyclyl and heteroaryl Wherein the substituents are phenyl, heteroaryl, heterocyclyl, -O-phenyl, fluorine, -CN, -C (O) NH ₂ , -C (O) (C ₁ -C ₃ -alkyl), -C (O) -phenyl, -N (C ₁ -C ₃ -alkyl) ₂ , -NH (C ₁ -C ₃ -alkyl), -NH ₂ , -NH-heteroaryl, -NH-C (O) -Heteroaryl, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkoxy and hydroxy, of which the phenyl, heterocyclyl and heteroaryl moieties are again fluorine, chlorine, bromine, oxo _{, -CF 3, -OCF 3, -NO} 2, -CN, phenyl, _{pyrimidinyl, -NHC (O) (C 1} -C 3 - alkyl), -COOH, hydroxy, C ₁ -C ₃ - alkyl , C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or N (C ₁ -C ₃ -alkyl) At least monosubstituted by ₂ , or R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted heterocyclyl, wherein the substituents are phenyl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, -C (O ) (C ₁ -C ₃ -alkyl), -C (O) -phenyl and hydroxy, of which the phenyl, heterocyclyl and heteroaryl moieties are again fluorine or C ₁ -C _3- At least monosubstituted by alkyl, R 6 is unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl or heteroaryl, wherein the substituents are fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NHC (O) (C _1- C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -O-heteroaryl, phenyl, -NH ₂ , -NH (C ₁ -C ₃ -alkyl),- N (C ₁ -C ₃ -alkyl) ₂ and heterocyclyl, wherein the phenyl, heteroaryl and heterocyclyl moieties are in turn fluorine, chlorine, bromine, hydroxy, C ₁ -C _3- At least monosubstituted by alkyl or C ₁ -C ₃ -alkoxy, R 7 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl and pyridinyl, wherein the substituents are fluorine, chlorine, bromine, hydroxy, C ₁ -C ₃ -alkyl And C ₁ -C ₃ -alkoxy, Heteroaryl is pyridinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl, 1,3-benzodioxolyl, triazolyl, thiazolyl, isoxazolyl, pi Rollyl, pyrazinyl, oxazolyl, pyridazinyl, quinolinyl, isoquinolyl, benzofuranyl, 3-oxo-1,3-dihydroisobenzofuranyl or 4,5,6,7-tetrahydrobenzo Thiazolyl, Or a physiologically acceptable compound of formula I, wherein the heterocyclyl is morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, dihydroisooxazolyl, piperazinyl, or tetrahydrofuranyl Salts thereof. The method according to claim 1 or 2, X is a single bond, NH or N (C ₁ -C ₃ -alkyl), R 1 is hydrogen or C ₁ -C ₃ -alkyl optionally substituted by hydroxy, chlorine, methoxy or 1, 2 or 3 fluorine atoms, R2 is hydrogen, fluorine, -OCF ₃ , hydroxy, methoxy, -NH ₂ or C ₁ -C ₃ -alkyl, Ar is unsubstituted or at least monosubstituted phenyl, thienyl, furanyl or pyridinyl, wherein the substituent is fluorine, chlorine, -CF ₃ , -OCF ₃ , C (O) (C ₁ -C ₃ -alkyl) , -NH ₂ , -NHC (O) (C ₁ -C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -CH ₂ -CH ₂ -CH _2- , -CH ₂ -OC (O)-, -CH ₂ -C (O) -O-, -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH ₂ -C (O) -NH-, -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and Selected from the group consisting of R3, R3 is -CH ₂ -NR4R5, -SO ₂ NR4R5, -C (O) NR4R5, -CH ₂ NHC (O) R6, -CH ₂ -NHSO ₂ R6 or -CH (OH) R7, R 4 and R 5 independently of one another are preferably a group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, indanyl, heterocyclyl and heteroaryl Wherein the substituent is phenyl, heteroaryl, heterocyclyl, -O-phenyl, fluorine, -CN, -C (O) NH ₂ , -C (O) (C ₁ -C ₃ -alkyl), -C (O) -phenyl, -N (C ₁ -C ₃ -alkyl) ₂ , -NH (C ₁ -C ₃ -alkyl), -NH ₂ , -NH-heteroaryl, -NH-C (O) -Heteroaryl, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkoxy and hydroxy, of which the phenyl, heterocyclyl and heteroaryl moieties are again fluorine, chlorine, bromine, oxo _{, -CF 3, -OCF 3, -NO} 2, -CN, phenyl, _{pyrimidinyl, -NHC (O) (C 1} -C 3 - alkyl), -COOH, hydroxy, C ₁ -C ₃ - alkyl , C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N ( C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or N (C ₁ -C ₃ -alkyl) ₂ At least monosubstituted by R4 and R5 together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted heterocyclyl, wherein the substituents are phenyl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, -C (O ) (C ₁ -C ₃ -alkyl), -C (O) -phenyl and hydroxy, of which the phenyl, heterocyclyl and heteroaryl moieties are again fluorine or C ₁ -C _3- At least monosubstituted by alkyl, R 6 is —CF ₃ or unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, pyridinyl, furanyl or phenyl, wherein the substituent is fluorine, —NHC (O) (C ₁ -C ₃ -alkyl) , Hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy and -O-pyridinyl, R 7 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl and pyridinyl, wherein the substituents are fluorine, chlorine, bromine, hydroxy, C ₁ -C ₃ -alkyl And C ₁ -C ₃ -alkoxy, Heteroaryl is pyridinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl, 1,3-benzodioxolyl, triazolyl, thiazolyl, isoxazolyl, pi Rollyl, pyrazinyl, oxazolyl, pyridazinyl, quinolinyl, isoquinolyl, benzofuranyl, 3-oxo-1,3-dihydroisobenzofuranyl or 4,5,6,7-tetrahydrobenzo Thiazolyl, Or a physiologically acceptable compound of formula I, wherein the heterocyclyl is morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, dihydroisooxazolyl, piperazinyl, or tetrahydrofuranyl Salts thereof. The method according to any one of claims 1 to 3, X is a single bond, NH or N (C ₁ -C ₃ -alkyl), R 1 is hydrogen or C ₁ -C ₃ -alkyl, R2 is hydrogen, Ar is monosubstituted phenyl, thienyl, furanyl or pyridinyl, wherein the substituents are fluorine, chlorine, -CF ₃ , -OCF ₃ , -C (O) (C ₁ -C ₃ -alkyl), -NH ₂ , -NHC (O) (C ₁ -C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N Is selected from the group consisting of (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and R ₃ , the substituent and X are in a meta position relative to each other, R 3 is —CH ₂ —NR ₄ R ₅ , —CH ₂ NHC (O) R 6, —CH ₂ —NHSO ₂ R 6, —C (O) NR ₄ R 5 or —CH (OH) R 7, R 4 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, indanyl, heterocyclyl and heteroaryl, wherein the substituents are Phenyl, heteroaryl, heterocyclyl, -O-phenyl, fluorine, -CN, -C (O) NH ₂ , -C (O) (C ₁ -C ₃ -alkyl), -C (O) -phenyl, -N (C ₁ -C ₃ - _{alkyl) 2, -NH (C 1 -C} 3 - alkyl), -NH _2, -NH- heteroaryl, -NH-C (O) - heteroaryl, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkoxy and hydroxy, of which the phenyl, heterocyclyl and heteroaryl moieties are again fluorine, chlorine, bromine, oxo, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, phenyl, pyrimidinyl, -NHC (O) (C ₁ -C ₃ -alkyl), -COOH, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy , -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C ₁ -C ₃ -alkyl) ₂ can be substituted, R 5 is hydrogen, R 4 and R 5 together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted heterocyclyl, wherein the substituents are phenyl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine, -C ( O) (C ₁ -C ₃ -alkyl), -C (O) -phenyl and hydroxy, wherein the phenyl, heterocyclyl and heteroaryl moieties of these substituents are again fluorine or C ₁ -C ₃ At least monosubstituted by alkyl, R 6 is —CF ₃ or unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, pyridinyl, furanyl or phenyl, wherein the substituent is fluorine, —NHC (O) (C ₁ -C ₃ -alkyl) , Hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy and -O-pyridinyl, R 7 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl, phenyl and pyridinyl, wherein the substituents are fluorine, chlorine, bromine, hydroxy, C ₁ -C ₃ -alkyl And C ₁ -C ₃ -alkoxy, Heteroaryl is pyridinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, benzimidazolyl, pyrazolyl, thiazolyl, isoxazolyl, pyrrolyl, pyrazinyl, 3-oxo-1,3-di Hydroisobenzofuranyl or 4,5,6,7-tetrahydrobenzothiazolyl, Or a physiologically acceptable compound of formula I, wherein the heterocyclyl is morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, dihydroisooxazolyl, piperazinyl, or tetrahydrofuranyl Salts thereof. The method according to any one of claims 1 to 4, X is a single bond or NH, R 1 is hydrogen or C ₁ -C ₃ -alkyl, R2 is hydrogen, Ar is monosubstituted phenyl, thienyl, furanyl or pyridinyl, wherein the substituents are fluorine, chlorine, -CF ₃ , -OCF ₃ , -C (O) (C ₁ -C ₃ -alkyl), -NH ₂ , -NHC (O) (C ₁ -C ₃ -alkyl), hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -NH (C ₁ -C ₃ -alkyl), -N Is selected from the group consisting of (C ₁ -C ₃ -alkyl) ₂ , -SO ₂ (C ₁ -C ₃ -alkyl) and R ₃ , the substituent and X are in a meta position relative to each other, R3 is -CH ₂ -NR4R5, -C (O) NR4R5 or -CH (OH) R7, R 4 is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C ₁ -C ₁₀ -alkyl, cyclohexenyl, indanyl, phenyl, pyrrolidinyl, pyrrolyl, pyrazolyl, furanyl and piperidinyl Wherein the substituent is fluorine, -CN, -C (O) NH ₂ , -O-phenyl, -C (O) -phenyl, -N (CH ₃ ) ₂ , C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, hydroxy, unsubstituted or at least monosubstituted phenyl, pyrimidinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl, morpholinyl , Pyrrolidinyl, 1,3-benzodioxolyl, piperidinyl, tetrahydropyranyl, triazolyl, thiazolyl, thiazolidinyl, isoxoxazolyl and dihydroisooxazolyl, and these substituents is again a fluorine, chlorine, _{oxo, CF 3, -OCF 3, -NO} 2, phenyl, _{pyrimidinyl, -NHC (O) CH 3,} -COOH, hydroxyl, C ₁ -C ₃ - alkyl, C ₁ - C ₃ - alkoxy _{, -SO 2 NH 2, -C (} O) is substituted with NH ₂ or -N (CH _{3) 2,} R5 is hydrogen, R 4 and R 5 together with the nitrogen atom to which they are attached form a radical selected from the group consisting of unsubstituted or at least monosubstituted piperidinyl, pyrrolidinyl, morpholinyl and piperazinyl, wherein the substituent is fluorine , -C (O) (C ₁ -C ₃ -alkyl), oxo, C ₁ -C ₃ -alkyl, hydroxy, unsubstituted or at least monosubstituted phenyl, imidazolyl, pyridinyl, pyrimidinyl, pipe Selected from the group consisting of lidinyl and pyrrolidinyl, these substituents are again substituted with fluorine or C ₁ -C ₃ -alkyl, A compound of formula (I) or a physiologically acceptable salt thereof, wherein R 7 is hydrogen. The method according to any one of claims 1 to 5, X is a single bond or NH, R 1 is hydrogen or C ₁ -C ₃ -alkyl, R2 is hydrogen, Ar is monosubstituted phenyl, thienyl, furanyl or pyridinyl, wherein the substituents are fluorine, chlorine, -OCF ₃ , -C (O) CH ₃ , -NHC (O) CH ₃ , hydroxy, -N Is selected from the group consisting of (CH ₃ ) ₂ , ethoxy, -SO ₂ CH ₃ and R _3, and the substituents and X are at meta positions relative to each other, R3 is -CH ₂ -NR4R5, R 4 is unsubstituted or at least monosubstituted C ₁ -C ₆ -alkyl wherein the substituents are —N (CH ₃ ) ₂ , hydroxy, unsubstituted or at least monosubstituted phenyl, pyrimidinyl, imidazolyl, Indolyl, benzimidazolyl, pyrazolyl and pyrrolidinyl; these substituents are in turn -NHC (O) CH ₃ , C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy,- Is substituted with SO ₂ NH ₂ or —C (O) NH ₂ and R 5 is hydrogen; R 4 and R 5 together with the nitrogen atom to which they are attached form a radical selected from the group consisting of unsubstituted or at least monosubstituted pyrrolidinyl, piperidinyl and piperazinyl, wherein the substituents are C ₁ -C ₃ A compound of formula (I) or a physiologically acceptable salt thereof, selected from the group consisting of alkyl, hydroxy and pyrrolidinyl. The compound according to any one of claims 1 to 5, wherein 4- (3-methanesulfonylphenylamino) -3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (3-acetylphenylamino) -3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (5-butylaminomethylfuran-2-yl) -3 -Methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 3-methyl-4- (5-pyrrolidin-1-ylmethylfuran-2-yl) -5,6 , 7,8-tetrahydro-2H-isoquinolin-1-one, 4- [5- (3-hydroxypyrrolidin-1-ylmethyl) furan-2-yl] -5,6,7,8 -Tetrahydro-2H-isoquinolin-1-one, 4- (5-{[(4-pyrrolidin-1-ylpiperidin-1-ylmethyl) amino] methyl} furan-2-yl) -5 , 6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- {5-[(2-dimethylaminoethylamino) methyl] -furan-2-yl) -5,6,7,8 -Tetrahydro-2H-isoquinolin-1-one, 4- {5-[(2-hydroxy-2-phenylethylamino) methyl] furan-2-yl} -5,6,7,8-tetrahydro -2H-isoquinolin-1-one, 4- (5-{[(4-methylpipera Gen-1-ylmethyl) amino] methyl} furan-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (5-{[(1-methyl- 1H-pyrazol-4-ylmethyl) amino] methyl} furan-2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one, 4- (5-butylaminomethylfuran -2-yl) -5,6,7,8-tetrahydro-2H-isoquinolin-1-one and 4- (5-hydroxymethylfuran-2-yl) -3-methyl-5,6,7 , 8-tetrahydro-2H-isoquinolin-1-one, or a physiologically acceptable salt thereof. The compound according to any one of claims 1 to 7, or a physiologically acceptable salt thereof, used as a medicament. Use of a compound according to any one of claims 1 to 7 or a physiologically acceptable salt thereof for preparing a drug which is a PARP inhibitor. Tissue damage resulting from cell death due to cell damage or necrosis or apoptosis, neuronal tissue damage or abnormality, cerebral ischemia, brain trauma, stroke, reperfusion injury, schizophrenic and degenerative neurological diseases, vascular stroke, cardiovascular disease, myocardial infarction , Myocardial ischemia, experimental allergic encephalomyelitis (EAE), multiple sclerosis (MS), ischemia associated with cardiac surgery, macular degeneration with age, arthritis, atherosclerosis, cancer, degenerative diseases of skeletal muscle with aging, diabetes mellitus and diabetic myocardium Use of a compound according to claim 1 or a physiologically acceptable salt thereof for the manufacture of a medicament for the prophylaxis and / or treatment of a disease selected from the group consisting of infarctions. Use according to claim 10, wherein the disease is selected from the group consisting of cerebral ischemia, reperfusion injury, cardiovascular abnormalities, myocardial infarction, myocardial ischemia and ischemia associated with heart surgery. Use according to claim 10 or 11, wherein the disease is myocardial infarction. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 7 or a physiologically acceptable salt thereof and a physiologically acceptable carrier. The method according to claim 13, wherein the pill, tablet, pill, swallowable tablet, granule, capsule, hard or soft gelatin capsule, water soluble liquid, alcoholic liquid, oily liquid, syrup, emulsion, suspension, suppository, flavor Tablets, injections or infusions, ointments, tinctures, creams, lotions, powders, sprays, transdermal therapeutic systems, nasal sprays, aerosols, aerosol blends, microcapsules, implants, rods or Pharmaceutical compositions present as patches. Reacting the compound of formula X with a suitable reagent, removing the methyl group to provide a compound of formula XI, and When R ″ of the compound of formula XI is —CHO and R 3 is —CH ₂ —NR ₄ R 5, the compound of formula XI is reacted (1) with a suitable amine in the presence of a reducing agent, or When R ″ of the compound of formula (XI) is —CHO and R 3 is —CH ₂ OH, the compound of formula (XI) is reduced (2) with a suitable reducing agent, or When R ″ of the compound of formula XI is —CHO and R 3 is —CH ₂ NHC (O) R 6 or —CH ₂ NHSO ₂ R 6, the compound of formula XI is reductively aminated with ammonium acetate, followed by suitable acid chloride, Coupling with a suitable acid or a suitable sulfonyl chloride (3), or If R "of the compound of formula XI is -COOH and R3 is -C (O) NR4R5, reacting (4) the compound of formula (XI) with a suitable amine in the presence of a condensing agent According to any one of claims 1 to 7, characterized in that in formula (I), X is a single bond and the substituent Ar is at least monosubstituted by R 3. Process for the preparation of compounds of formula (I).

Compound of Formula XI.

In the above formula (XI), R 1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF ₃ , or hydroxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms, R2 is hydrogen, fluorine, -CN, hydroxy, methoxy, -OCF ₃ , -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ , or hydroxy Oxy, chlorine, methoxy or C ₁ -C ₃ -alkyl optionally substituted by 1, 2 or 3 fluorine atoms, R8 is C ₁ -C ₈ -alkoxy, -O-phenyl, C ₁ -C ₃ -alkyl, -NH ₂ , -NH (C ₁ -C ₃ -alkyl), -N (C ₁ -C ₃ -alkyl) ₂ or phenyl and the phenyl moiety is again fluorine, chlorine, bromine, oxo, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, aryl, heteroaryl, -NHC (O) (C ₁ -C ₃ -alkyl ), -COOH, hydroxy, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₃ -alkyl), -SO ₂ N (C ₁ -C ₃ -alkyl) ₂ , -C (O) NH ₂ , -C (O) NH (C ₁ -C ₃ -alkyl), -C (O) N (C ₁ -C ₃ -alkyl) ₂ , At least monosubstituted by -SO ₂ (C ₁ -C ₃ -alkyl), -NH ₂ , -NH (C ₁ -C ₃ -alkyl) or -N (C ₁ -C ₃ -alkyl) ₂ , Ar is aryl or heteroaryl, and such aryl or heteroaryl is fluorine, chlorine, bromine, -CF ₃ , -OCF ₃ , -NO ₂ , -CN, -C (O) R 8, -NH ₂ , -NHC (O ) (C ₁ -C ₆ -alkyl), hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -CH ₂ -CH ₂ -CH ₂ , -CH ₂ -OC (O)-, -CH ₂ -C (O) -O-, -CH ₂ -NH-C (O)-, -CH ₂ -N (CH ₃ ) -C (O)-, -CH ₂ C (O) -NH- , -NH (C ₁ -C ₆ -alkyl), -N (C ₁ -C ₆ -alkyl) ₂ , -SO ₂ (C ₁ -C ₆ -alkyl), heterocyclyl, heteroaryl and aryl Optionally substituted by one or more substituents selected from among which heterocyclyl, aryl and heteroaryl are, in turn, substituted with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, fluorine, chlorine, bromine, trifluoromethyl At least monosubstituted by trifluoromethoxy or OH, R "is -COOH, -CHO or -SO ₂ Cl, Heteroaryl is a 5 to 10 membered aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S, Heterocyclyl is a 5-10 membered non-aromatic monocyclic or bicyclic heterocycle comprising one or more heteroatoms selected from N, O and S, Aryl is a 5-10 membered aromatic monocycle or bicycle. The method of claim 16, R 1 is hydrogen or C ₁ -C ₃ -alkyl, R2 is hydrogen, Ar is phenyl, furanyl, thienyl or pyridinyl, and the R ″ and tetrahydroquinolinone moieties are in meta positions relative to each other, A compound of formula XI wherein R "is -CHO or -COOH.